U.S. patent number 5,164,189 [Application Number 07/667,992] was granted by the patent office on 1992-11-17 for single layer transdermal drug administration system.
This patent grant is currently assigned to G. D. Searle & Co.. Invention is credited to Hana Berger, Bahram Farhadieh, Rajeev D. Gokhale, Joseph Vallner.
United States Patent |
5,164,189 |
Farhadieh , et al. |
November 17, 1992 |
**Please see images for:
( Certificate of Correction ) ** |
Single layer transdermal drug administration system
Abstract
A patch for the transdermal delivery of pharmaceutical drugs.
The patch is characterized by having a single mass of elastomer in
which the active drug and a percutaneous absorption enhancer are
homogeneously dispersed throughout. The patch is especially well
suited to delivering the beta.sub.2 adrenergic agonist drug
albuterol.
Inventors: |
Farhadieh; Bahram
(Libertyville, IL), Gokhale; Rajeev D. (Vernon Hills,
IL), Berger; Hana (Lincolnshire, IL), Vallner; Joseph
(Mountainview, CA) |
Assignee: |
G. D. Searle & Co.
(Chicago, IL)
|
Family
ID: |
23687946 |
Appl.
No.: |
07/667,992 |
Filed: |
March 11, 1991 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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425766 |
Dec 4, 1989 |
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Current U.S.
Class: |
424/448; 424/449;
424/447 |
Current CPC
Class: |
A61P
37/08 (20180101); A61P 43/00 (20180101); A61K
9/7092 (20130101); A61P 3/00 (20180101); A61P
11/08 (20180101); A61P 15/04 (20180101); A61K
47/10 (20130101); A61K 9/7069 (20130101); Y10S
514/946 (20130101) |
Current International
Class: |
A61K
9/70 (20060101); A61K 47/10 (20060101); A61F
013/00 () |
Field of
Search: |
;424/449,448,447,486 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0130839 |
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Jan 1983 |
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EP |
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0137545 |
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Apr 1985 |
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EP |
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0150021 |
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Jul 1985 |
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EP |
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2375295 |
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Jul 1978 |
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FR |
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59-204650 |
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Nov 1984 |
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JP |
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Other References
Tapash Ghosh et al., "Transdermal Drug Delivery Systems for a Model
Beta Bocker: Levobunolol", Pharmaceutical Research, 7, 9, S-190
(1990). .
R. Gokhale et al., "Bioavailability of a Transdermal Albuterol
Patch", Pharmaceutical Research, 6, 9, S-167 (1989). .
Tapash Ghosh et al., "Diffusion of Some Selected Beta-Blockers
Across the Hairless Mouse Skin", Pharmaceutical Research, 3, 5, 52S
(1986)..
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Horne; Leon R.
Attorney, Agent or Firm: Hastreiter; Roberta L. Matukaitis;
Paul D.
Parent Case Text
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of application U.S. Ser.
No. 425,766 filed on Dec. 4, 1989, entitled, "Novel Single Layer
Transdermal Drug Administration System," now abandoned.
The present invention comprises a transdermal patch for the
administration of drugs percutaneously. In particular, the
invention is useful for the administration of the drug albuterol, a
.beta..sub.2 adrenergic agonist, which is useful, among other
things, in the treatment of asthma by virtue of its action of
inducing bronchodilation.
The practicality of administering a given drug percutaneously on a
continuous basis depends upon the concentration of drug in the
blood that is required to provide the desired pharmacologic effect,
the degree to which the skin is permeable to the drug, and the
amount of skin surface area that is available for drug
administration.
The skin surface area which is available for drug administration,
while theoretically being unlimited, is, for practical reasons,
typically confined to a range of from about five square centimeters
to about 100 square centimeters. With the available skin surface
area fixed within this range, the matter then narrows as to whether
sufficient drug will pass through that much skin surface area to
provide the desired therapy. If it will, then it may not be
difficult to effectively administer the drug percutaneously. If,
however, the inherent permeability of the skin to the drug is so
high or so low that too much or too little drug will pass through
that area of skin, then the rate of administration of the drug to
the skin must be controlled, or the permeability of the skin to the
drug must be increased, as the case may be, to make percutaneous
administration practical.
The present invention involves a drug delivery system in which the
percutaneous administration of the active drug component is
enhanced by the presence of a diffusion enhancer.
Systemically active drugs are conventionally administered either
orally or by injection, with the primary objective of either mode
being to achieve a given desired blood level of drug in circulation
over a period of time.
These prior conventional methods of administering drugs to
patients, however, possess certain shortcomings resulting in the
failure to this goal.
The oral route of drug administration, for example, is inadequate
for several reasons, even if the drug is administered to the
patient at periodic intervals according to a well-defined
schedule.
The rate of absorption of drug through the gastrointestinal tract
is affected by both the contents in the tract and the passage of
time as the drug travels through the small intestine. Therefore,
such variables as whether the drug is administered before or after
eating, and the type and quantity of food eaten, for example, high
or low fat content, or whether the drug is administered before or
after a bowel movement, affect the rate of absorption of the drug
which takes place in the small intestine.
Additionally, the time of passage of drug through the small
intestine is affected by the rate of peristaltic contraction,
adding further uncertainty.
Also important is the rate of circulation of blood to the small
intestine, and the fact that many drugs administered by this route
are rendered inactive by gastric acid and digestive enzymes of the
gastrointestinal tract or liver, where the drug can be metabolized
to an inactive product.
These factors make it difficult to achieve a desired time course of
concentration of drug in the blood.
The most widely-used dosage form of albuterol, an
orally-administered, instant-release (IR) tablet, is administered
to a patient every 6 hours. The controlled-release (CR) albuterol
tablet is administered to a patient every 12 hours.
A significant disadvantage associated with the oral administration
of albuterol is that orally-administered albuterol undergoes
extensive first pass metabolism, probably in the gastrointestinal
tract, with the result that the bioavailability of the drug
formulation is reduced from a potential bioavailability of 100
percent to as low as 10 percent.
The most inevitable result of the oral administration of drugs
through the gastrointestinal tract is that the level of drug in
circulation surges to a peak level at the time the drug is
administered, followed by a decline in drug concentration in the
blood and body compartments. Thus, a plot of a drug in circulation
versus time after the administration of several tablets of the drug
per day will have the appearance of a series of peaks which may
surpass the toxic threshold of the drug, and valleys which may fall
below the critical point needed to achieve the desired
pharmacologic or therapeutic effect of the drug, rather than a
horizontal straight line indicating a steady-state concentration
(C.sub.ss) of the drug in circulation.
The administration of drugs by injection likewise entails certain
disadvantages. For example, very strict asepsis must be maintained
in order to avoid infection of the blood, the vascular system and
the heart. Drug administration by poor intravenous injection
technique may result in perivascular injection, when that was not
intended. The typical result of injection of a drug into the blood
is a sudden rise in the blood concentration of the drug followed by
an uncontrollable decline in drug concentration. Additionally,
administration of drugs by injection is inconvenient and
painful.
Other dosage forms for systemic administration of drugs, such as
rectal suppositories and sublingual lozenges, also produce
non-uniform levels of the therapeutic agent in circulation. These
dosage forms require great patient cooperation and have low patient
acceptability, resulting in decreased patient compliance with a
prescribed drug regimen, which is the most common failure of drug
therapy.
To avoid the problems discussed above, a new branch of drug
delivery has developed in which systemically-active drugs are
administered through the skin or mucosa of a patient. Uncertainties
of administration through the gastrointestinal tract, and the
inconvenience of administration by injection, are decreased or
eliminated by this system of drug administration. The ease of
application, and simplicity of removal, of such a drug delivery
system produces a desirable psychological effect on the patient.
This means better patient cooperation, resulting in more effective
therapy. Because a high concentration of drug never enters the
body, problems with pulse entry (varying levels of drug in the
patient's circulation, depending upon the time of drug
administration) are overcome.
Despite these advantages of administering systemically-active drugs
through the skin, many problems exist with prior art devices
designed for this purpose. Many such devices do not provide a
continuous administration of drug to the patient, or a continuous
delivery rate. Also, many such devices are irritating to the
patient's skin or mucosa and/or have limited application to a
relatively narrow group of therapeutic drugs. Frequently, new
application systems must be designed for drugs which are
incompatible with prior art application systems.
The release of a drug from a topical preparation can be materially
affected by the vehicle in which it is applied. Correct formulation
of a topical agent will ensure that it exerts its maximal activity,
while an incorrect formulation of the agent may reduce its
activity, or even render a potent drug essentially ineffective.
The primary requirement for topical drug therapy is that a drug
incorporated in a vehicle reach the skin surface at an adequate
rate and in sufficient amounts. The drugs must then penetrate the
outer horny layer of the skin.
Drug penetration through the skin depends upon release of the drug
from the topical delivery device and transport of the drug across
the skin barrier. In most cases, the rate-limiting step is skin
transport. However, formulation changes can affect both of these
steps.
Transport of drug substances through the skin is affected by a
variety of factors. For diffusion to occur, the drug must be in
solution. Thus, solubility of the drug in the fluids in and around
the epidermal cells is of great significance.
The polarity of the drug molecules must also be considered. When
hydrated, the stratum corneum contains approximately 75% water, 20%
protein and 5% lipid. During hydration, water accumulates near the
outer surface of the protein filaments. Polar molecules are
believed to pass through this aqueous layer, while nonpolar
molecules probably dissolve in, and between, the protein
filaments.
The oil-water partition coefficient is also important. If a
substance is more soluble in the stratum corneum than in the
vehicle in which it is dissolved, then transfer to the former will
be favored. In vitro and in vivo studies support the postulate that
the release of a drug will be facilitated by using vehicles having
a low affinity for the penetrant. Thus, in formulation, care is
necessary to ensure that the benefits of drug solubility in
relation to skin penetration are not reduced by the use of
excipients which have too high an affinity for the drug.
A further factor which has been shown to influence drug
effectiveness, and which can be manipulated by the formulator, is
the level of hydration of the stratum corneum. Hydration results
from water diffusing from underlying epidermal layers or from
perspiration that accumulates under an occlusive vehicle. In
general, increasing the moisture content of the stratum corneum
increases the rate of passage of all substances which penetrate the
skin.
Researchers working in the art have conducted studies of the
effects of vehicles containing substances which materially affect
skin penetration. A range of agents has been recorded as having
accelerant action, in particular propylene glycol, surface active
agents, dimethylsulfoxide, and dimethylacetamide. These substances,
however, have certain drawbacks, including skin irritation
potential. Their use to date has been limited.
B. Idson, Cosmetics and Toiletries 95, 59 (1980), has concluded
that the factors affecting drug penetration into the skin and,
consequently, in most cases effectiveness, are complex. The vehicle
that provides ideal conditions for one drug may prove
unsatisfactory for another.
The present invention seeks to overcome prior problems with the
continuous administration of a drug to a patient, and with the
delivery rate of the drug in general, and has been found to work
particularly well with adrenergic agonists, and especially well
with albuterol, a selective .beta..sub.2 adrenergic agonist.
Another object of this invention is to provide a device for the
administration of albuterol to a patient in a reliable and
easily-applied device for continuously administering the drug to
the patient in controlled quantities through the patient's intact
skin or mucosa.
Another object of this invention is to provide for such a drug
delivery device which will cause little, if any, dermal or mucosal
irritation to the patient.
Another object of this invention is to provide a drug delivery
device which will be especially useful and acceptable in pediatric
patients and geriatric patients.
A further object of this invention is to provide for a unitary,
non-lamellar, single-layered drug delivery device.
Yet another object of this invention is to provide a drug
administration device which will provide a continuous dosing of the
drug to the patient over a 24-hour period.
The transdermal drug administration patches of the present
invention generally provide a continuous administration of drug to
the patient. In addition, these patches generally cause little or
no dermal or mucosal irritation to the patient. Both of these
qualities are significant advantages of the patches of the present
invention in comparison with many of the transdermal drug
administration systems known in the art. Many of the prior art
devices designed to deliver systemically active drugs through the
skin or mucosa of a patient fail to provide a continuous
administration of the drug to the patient, and/or do not provide a
continuous delivery rate of the drug to the patient. Even if a
transdermal patch does administer a particular drug appropriately
through the skin or mucosa of a patient, the patch will not be a
desirable form of administration for the drug if the patch is
irritating to the patient's skin or mucosa.
Prior to the invention of the transdermal albuterol patches
described herein, researchers working in the field were unable to
successfully deliver albuterol to a patient by means of a
transdermal patch.
The transdermal albuterol patches of the present invention feature,
in addition to the benefits already described above, a 100% skin
bioavailability of drug to a patient, a good margin of safety in
pediatric and geriatric patients and ease of administration.
Albuterol administered transdermally through a patch of the
invention is useful for actual asthma therapy, rather than merely
for prophylaxis. It is also useful in both pediatric age groups and
geriatric populations, both of which require simple-to-administer
regimens that do not rely on the responsibility or memory of the
patient to comply with several daily dosage administrations of the
drug, as is often needed with conventional tablets or capsules of
albuterol. Transdermal albuterol therapy would also be useful after
the treatment of an acute asthma attack to prevent the exacerbation
of such an attack. Clinically, it would also be useful either as a
substitute for intravenous therapy or as an improvement over oral
therapy.
In addition to being convenient, transdermal albuterol therapy has
a significant margin of safety. Significantly, an on-going therapy,
such as with sustained-release oral formulations, could be
interrupted if the average plasma level of the drug were too high.
Once the patient was stabilized at a lower plasma level of drug,
the transdermal albuterol patch would be beneficial to maintain
consistent plasma levels of albuterol at a more desirable lower
level.
Additionally, albuterol can be used transdermally as a tocolytic
(obstetric) agent. Preterm labor occurs in approximately 10% of
pregnancies. Commonly, beta-mimetic agents are employed for preterm
labor. Albuterol is currently used for preterm labor, with the
plasma albuterol levels needed for uterine relaxation being 8 to 33
nanograms of drug per milliliter. Such levels are within the range
of albuterol delivered by the transdermal albuterol patches of the
present invention.
The albuterol patches of the present invention also have the
potential advantage of safety over the intravenous route of drug
administration, and the further advantage of a more uniform dosing
of the drug to the patient in comparison with the oral route of
drug administration, during the sensitive and critical period
during which labor occurs. Such a use of an albuterol patch of the
invention may be adjunctive with bed rest and intravenous and oral
agents, or may be primary therapy as a substitution for intravenous
beta-mimetic agents.
Additionally, a transdermal albuterol patch of the invention may
find usage as an emergency therapy for the treatment of urticaria
(hives).
The usefulness of albuterol as a bronchodilator is not limited to
the treatment of asthma. Albuterol can also be used as a
bronchodilator in the treatment of bronchitis, chronic obstructive
pulmonary disease and other obstructive pulmonary diseases.
Claims
What is claimed is:
1. A monolayer patch for the transdermal administration of
albuterol comprising:
a. an elastomeric matrix, said elastomeric matrix being present in
an amount ranging from about 25 to about 85 per cent, weight to
weight;
b. albuterol, said albuterol being present in an amount ranging
from about 2 to about 30 per cent, weight to weight; and
c. a diffusion enhancer, said diffusion enhancer being a normal
hydrocarbon alcohol having from about 1 to about 20 carbon atoms,
and said diffusion enhancer being present in an amount ranging from
about 3 to about 30 per cent, weight to weight;
said patch having a thickness of between about 0.05 and about 0.5
millimeters, and said patch having an area which is in the range of
from about 1 to about 100 square centimeters.
2. The patch according to claim 1 wherein said elastomeric matrix
is present in an amount ranging from about 65 to about 90 per cent,
weight to weight.
3. The patch according to claim 1 wherein said elastomeric matrix
is a silicone elastomer.
4. The patch according to claim 1 wherein said diffusion enhancer
is n-dodecanol.
5. The patch according to claim 2 wherein said diffusion enhancer
is n-dodecanol.
6. The patch according to claim 5 said n-dodecanol is present in an
amount ranging from about 6 to about 15 per cent, weight to
weight.
7. The patch according to claim 6 wherein said albuterol is present
in an amount ranging from about 8 to about 24 per cent, weight to
weight.
8. The patch according to claim 7 wherein said albuterol is present
in an amount ranging from about 12 to about 20 per cent, weight to
weight.
9. The patch according to claim 3 wherein said diffusion enhancer
is n-dodecanol.
10. The patch according to claim 1 wherein said diffusion enhancer
is n-dodecanol.
11. The patch according to claim 1, additionally comprising a
plasticizer.
12. The patch according to claim 11 said plasticizer is a
polyol.
13. The patch according to claim 12 wherein said polyol is
glycerol.
14. The patch according to claim 11, additionally comprising a
solubilizer.
15. The patch according to claim 14 wherein said solubilizer is a
normal hydrocarbon alcohol.
16. The patch according to claim 15 wherein said hydrocarbon
alcohol is n-hexanol.
17. The patch according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13 or 14, additionally comprising a curing catalyst for said
elastomeric matrix.
18. The patch according to claim 17 additionally comprising a
backing member.
19. The patch according to claim 18 additionally comprising a
protective release film and/or a low adhesion back side
coating.
20. A method of administering albuterol to a mammal in need
thereof, comprising the step of administering to the skin or
mucosal areas of said mammal a patch according to claim 1, 3, 4, 6,
9 or 10.
21. A method of treating bronchial constriction and/or urticaria in
a mammal in need thereof, comprising the step of applying to the
skin or mucosal areas of such animal a patch according to claim 1,
3, 4, 6, 9, or 10.
22. A method of delaying premature uterine contractions in a
pregnant mammal in need thereof, comprising the step of applying to
the skin or mucosal areas of said mammal a patch according to claim
1, 3, 4, 6, 9 or 10.
23. A double layer patch for the transdermal administration of
albuterol comprising an albuterol layer and a diffusion enhancer
layer, said albuterol layer comprising:
a. an elastomeric matrix, said elastomeric matrix being present in
an amount ranging from about 25 to about 95 per cent, weight to
weight, and
b. albuterol, said albuterol being present in an amount ranging
from about 2 to about 30 per cent, weight to weight,
and said diffusion enhancer layer comprising:
a. an elastomeric matrix, said elastomeric matrix being present in
an amount ranging from about 25 to about 95 per cent, weight to
weight, and
c. a diffusion enhancer, said diffusion enhancer being a normal
hydrocarbon alcohol having from about 1 to about 20 carbon atoms,
and said diffusion enhancer being present in an amount ranging from
about 3 to about 30 per cent, weight to weight;
said patch having a thickness of between about 0.05 and about 0.5
millimeters, and said patch having an area which is in the range of
from about 1 to about 100 square centimeters.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plot of the in vitro transfer of albuterol
transdermally through the skin of a hairless mouse contained in a
Franz Diffusion Cell Assembly (Example 1(a) versus time, showing
how various adjuvant agents affect the flux of albuterol through
the mouse skin. It can be seen that ethanol was the most effective
agent when compared with prior art agents, such as Azone and
isopropyl alcohol (IPA).
FIG. 2 is the same type of plot as FIG. 1, except that the agents
tested are normal hydrocarbon alcohols. It can be seen that, in
general, agent effect on albuterol flux increases as the chain
length of the alcohol increases.
FIG. 3 is a plot of albuterol concentrations versus time following
albuterol transdermal patch dissolution in a Hanson's Dissolution
Test Apparatus (Example I(b)) showing the in vitro release of
albuterol from the patches. The error bars represent the standard
deviation of the mean.
--Represents a single-layer albuterol transdermal patch (Example 2)
(n=3).
.quadrature.--Represents a double-layer albuterol transdermal patch
(Example 3) (n=6).
FIG. 4 is a plot of serum albuterol concentrations versus time
following the intravenous (n=4) (.quadrature.) (Example 1(d)), and
single-layer (n=4) ( ) and double-layer (n=3) ( ) transdermal patch
(Example I(e)) administration of albuterol in Rhesus monkeys. The
error bars represent the standard deviation of the mean.
FIG. 5 shows how "Area under the curve" (AUC) values [values of the
amount of albuterol int eh serum at a given point in time
(ng.mL.sup.-1.hours)] were calculated using the standard
trapezoidal rule and the following mathematical formula, as
described by M. Gibaldi et al. at Page 447: ##EQU1## where C.sub.1
represents the first concentration, C.sub.2 represents the second
concentration, T.sub.1 represents the first time and t.sub.2
SUMMARY OF THE INVENTION
The present invention comprises a transdermal patch for the
administration of drugs percutaneously.
The most preferred embodiment of this invention is a non-laminated
monolayer patch for the transdermal administration of a drug to a
patient comprising an elastomeric matrix material of predetermined
thickness and area; an active drug ingredient dispersed throughout
the matrix; and a diffusion enhancer dispersed throughout the
matrix.
Additionally, a suitable plasticizer and/or a solubilizing agent
for the active ingredient can conveniently be incorporated into the
patch.
Elastomeric Matrix Materials
Suitable elastomeric matrix materials for use in the patches of the
invention comprise the following polymers:
Polyethylene,
Polypropylene,
Polyethylene terephthalate,
Polyvinylidene fluoride,
Polymethyl methacrylate,
Polyurethane-polyamide copolymers,
Poly(2-hydroxyethyl methacrylate) (HEMA-hydrogel),
Polyalkyl acrylate esters (bioadhesive polymers),
Polyisobutylene (bioadhesive polymer),
Polydimethylsilicone with resin (bioadhesive polymer), and
Silicone elastomers.
The patches of the present invention preferably utilize a silicone
elastomer as the matrix. Silicone elastomers have alternating
silicon and oxygen atoms for a backbone. Double bonds are generally
absent in such a backbone and, therefore, the numerous forms of
stereoisomers ordinarily found in unsaturated hydrocarbon rubbers
do not have counterparts in the silicone rubbers. An especially
useful silicone elastomer for use in the patches of the invention
is Silastomer.TM. X7-3058, available from Dow Corning, Inc.,
Midland, Mich.
Generally, when an amine or an alcohol, such as albuterol or
n-dodecanol, respectively, is incorporated into certain elastomeric
matrix materials, such as silicone matrix materials, the alcohol
will have an undesirable effect on the cure of such materials, that
is, the effect of preventing the elastomeric matrix materials from
becoming or remaining hardened. Thus, the elastomeric matrix
materials would be expected to have a sticky consistency, or a
consistency like that of a petroleum jelly, and, thus, would not be
suitable for use in a transdermal drug administration patch.
Consequently, it was surprising and unexpected when elastomeric
matrix materials were discovered which would become hardened, and
remain in a suitably-hardened state, when albuterol and/or various
alcohol diffusion enhancers, such as n-dodecanol, were dispersed
therein.
In the most preferred embodiment of the present invention, the
active drug ingredient is albuterol, most preferably as the free
base.
Diffusion Enhancers
Diffusion enhancers for use in the patches of the invention are
suitably chosen from the group comprising:
Decymethyl Sulphoxide,
Hexylmethyl Sulphoxide,
Trimethyl phosphine oxide,
N,N-Dimethyl-m-toluamide,
Tetrahydrofuryl alcohol,
Dimethyl acetamide,
Propylene glycol,
n-methyl-2-pyrrolidone,
2-pyrolidone,
1-ethyl-2-pyrolidone,
Sodium lauryl phosphate,
Triethanol amine lauryl phosphate,
Poloxamer 231,
Polyoxyethylene 4 lauryl ether,
Poloxamer 182,
Urea,
Isopropyl myristate,
Isopropyl palmitate,
Butyrolactone,
Vanillin,
Stearyl alcohol, and the normal hydrocarbon alcohols.
Preferred diffusion enhancers for use in the patches of the
invention are normal hydrocarbon alcohols, with the most preferable
diffusion enhancer being n-dodecanol, dispersed throughout the
elastomeric matrix.
DETAILED DESCRIPTION OF THE INVENTION
Permeation of Drug through the Matrix Material
The present invention comprises a transdermal patch which is
suitable, by virtue of the rate-controlling materials employed
therein, for the predetermined controlled administration of drug to
the skin or mucosa of a mammal over a period of time. The patch of
the invention is applied to the patient's skin or mucosa and should
be in firm contact therewith so as to form a tight seal. Flow of
drug from the patch to the patient's skin or mucosa is metered
through the matrix material of the patch in accordance with the
laws of diffusion, as hereinafter discussed, at a predetermined
rate. In operation, drug molecules are continuously removed from
the patch, migrating through the patch to the skin or mucosa of the
patient, where the drug is absorbed and enters the patient's
circulation through the capillary network.
The rate of passage or permeation of drug through the elastomeric
matrix material of the patch is determined by the diffusive flux of
the drug molecules through the material, as is the case where the
material is of a solid nature in which the drug molecules can
dissolve in, and flow through, to a direction of lower chemical
potential.
The release rate of the drug can be controlled in accordance with
"Fick's First Law," depending on the design of the particular drug
transfer mechanism, which may vary according to certain variables,
such as the diffusivity and solubility of the drug being employed
in the diffusive medium, and the thickness of the matrix material
of the patch.
The mechanism of action of the diffusion enhancers described herein
may be to increase the diffusivity of active ingredient through the
patch matrix material. This mechanism of action shall be understood
to attach to the term "diffusion enhancer" as used herein.
Elastomeric Matrix Materials
Preferred elastomeric matrix materials for use in the patches of
the invention are the organopolysiloxane rubbers, commonly known as
silicone rubbers. Suitable silicone rubbers are the conventional
heat vulcanizable (curable) silicone rubbers and the room
temperature vulcanizable silicone rubbers. Room temperature
vulcanizable silicone rubbers will require the use of a curing
agent or catalyst. The most especially preferred silicone rubber
for use in the patches of the invention is Silastomer.TM. X7-3058,
available from Dow Corning, Inc. Other room temperature
vulcanizable silicone rubbers suitable for use in the patches of
the invention are also commercially available.
A typical catalyst that will cure silicone rubber at room
temperature is stannous 2-ethyl hexoate, which can be present in a
range of from about 0.0625% to about 0.5%.
Exemplary patents disclosing the preparation of silicone rubbers
are U.S. patent Nos. 2,541,137; 2,723,966; 2,863,846; 2,890,188;
2,927,907; 3,002,951 and 3,035,016.
Elastomer can be present in the patches of the invention in an
amount ranging from about 25 to about 95 per cent, weight to
weight. More preferably, it can be present in an amount ranging
from about 65 to about 90 per cent, weight to weight.
Catalysts
Catalysts which may be employed to cure the elastomeric matrix
material component of the patches of the invention include stannous
2-ethyl hexoate and Dow X7-3075 catalyst (Dow Corning, Inc.).
Catalyst can be present in the patches in a range of from about
0.0625% to about 0.5%, preferably in a range of from about 0.125%
to about 0.25%.
Patch Thickness and Area
The thickness of the transdermal patches of the invention can be
manipulated, as described in Examples 2 and 3 below, by any
conventional film casting apparatus, or other suitable apparatus.
Although the thickness of the patches may vary between about 0.05
and about 0.5 millimeters, the preferred range of thickness is
between about 0.20 and about 0.40 millimeters.
The area of the patches of the invention may also vary, and may be
in the range of from about 1 to about 100 square centimeters,
preferably from about 4 to about 16 square centimeters. The
patches, which are generally light yellow in color, may be square,
circular, rectangular or triangular in shape, or may be of other
shapes. The patches may be cut to an appropriate size and shape
with any sharp instrument, such as a razor blade.
Diffusion Enhancers
A diffusion enhancer is employed in the patches of the present
invention, with the most preferred diffusion enhancers being the
normal hydrocarbon alcohols of one to twenty carbon atoms. As the
chain length of the alcohol increases, the effectiveness of the
diffusion enhancer generally increases up to a point. The most
preferred diffusion enhancer for use in the patches of the
invention is n-dodecanol. n-dodecanol can be present in an amount
ranging from about 3 to about 30 per cent, weight to weight. More
preferably, it can be present in an amount ranging from about 6 to
about 15 per cent, weight to weight.
Plasticizers
Plasticizers are useful for increasing the plasticity of polymers.
In a preferred embodiment of the patches of the present invention,
a suitable plasticizer is employed. Preferred plasticizers include
diols, triols, and other polyols. The most preferred plasticizer is
glycerol.
Solubilizing Agents
In a preferred embodiment of the patches of the present invention,
a solubilizing agent for the active ingredient is employed.
Preferred solubilizing agents include the normal hydrocarbon
alcohols, with n-hexanol being the most preferred solubilizing
agent. n-hexanol can also act as a useful plasticizer.
Active Agents
The most preferred patch of the present invention comprises, out of
100%, Dow Silastomer.TM. X7-3058:Dow X7-3059 crosslinking agent
(97.86:2.14), 71.81%, w/w; albuterol, 15.98%, w/w; n-dodecanol,
9.99%, w/w; glycerol, 1.75%, w/w; and hexanol, 0.35%, w/w; with a
suitable organotin catalyst, 0.125%, w/w (generally stannous
2-ethyl hexoate).
All materials used in the patches of the present invention are
dispersed uniformly throughout the matrix material employed
therein. This dispersion results from the use of an elastomeric
matrix material.
The amount of active agent incorporated within the elastomeric
matrix material of the patches of the invention to obtain the
desired therapeutic effect will vary depending upon the desired
dosage of the active agent, the length of time the patch is to
remain on the skin or the body mucosa of the patient and the area
and thickness of the patch. Patient serum concentrations of the
active agent can thus be adjusted by varying the concentration of
the active agent in the patch, the length of time the patch is to
remain on the skin or body mucosa of the patient or the patch
size.
Because the patches of this invention are designed to control drug
administration for an extended period of time, ideally 24 hours or
more, absent toxicity concerns, there is no critical upper limit on
the amount of active agent incorporated into the patches. The lower
limit of the amount of active agent incorporated into the patches
is determined by the fact that sufficient amounts of the agent must
remain in the patches to maintain the desired dosage of the agent
for the particular patient being treated.
In order to achieve a therapeutic effect of albuterol in a human
adult suffering from a condition which is treatable with albuterol,
the patient serum concentration of albuterol should be in the range
of between about 2 and about 33 nanograms of albuterol per
milliliter of serum, and most preferably between about 4 and about
8 nanograms per milliliter. From about 4 to about 8 nanograms of
albuterol per milliliter is desirable for treating
bronchoconstriction, and from about 8 to about 33 nanograms of
albuterol per milliliter is desirable for using albuterol as a
tocolytic agent.
The effective rate of release of the active agent from the patches
of the invention to the skin or mucosa of a patient can be in the
range of from about 0.2 to about 2.0 milligrams of active agent per
square centimeter of skin or mucosa per day
(mg.cm.sup.-2.day.sup.-1). A more preferred range would be from
about 0.3 to about 0.85 milligrams of active agent per square
centimeter of skin or mucosa per day. The exact amount will depend
on the desired dosage of the active agent, as well as the condition
being treated.
Those skilled in the art can readily determine the rate of
permeation of active drug ingredient through a particular matrix
material, and through selected combinations of matrix materials, to
be employed in a patch of the invention. Standard techniques
employed for making such determinations are described in the
Encyclopedia of Polymer Science and Technology, Volumes 5 and 9,
Pages 65 to 85 and 795 to 807 (1968), and the references cited
therein, the disclosures of which are incorporated herein by
reference.
Albuterol (nonmicronized or micronized) can be present in the
patches of the invention in an amount ranging from about 2 to about
30 per cent, weight to weight. More preferably, it can be present
in an amount ranging from about 8 to about 24 per cent, weight to
weight, and most preferably, in an amount ranging from about 12 to
about 20 per cent, weight to weight.
Both nonmicronized and micronized albuterol may be employed in
making the transdermal patches of the invention. Both types of
albuterol work well, and neither type is preferable over the other.
However, it may be easier to obtain micronized albuterol.
Backing Members
Various occlusive and non-occlusive, flexible and non-flexible
backing members can be used in the patches of the present
invention, if desired.
Suitable backing members for use in the patches of the invention
include cellophane, cellulose acetate, ethylcellulose, plasticized
vinylacetate-vinylchloride copolymers, polyethylene terephthalate,
nylon, polyethylene, polypropylene, polyvinylidenechloride, paper,
cloth, foam and aluminum foil.
Protective Release Films and Foils
To prevent the passage of drug away from the exposed surface of a
patch of the invention prior to its use, the surface of the patch
generally can be covered with a protective release film or foil,
such as waxed paper.
To enhance the stability of the active compound(s) employed in a
patch of the invention, the patch is usually packaged between
hermetically-sealed polyethylene terephthalate films or aluminum
foils under an inert atmosphere, such as gaseous nitrogen.
Application of Patches
The patches of the invention are applied to the skin of patients. A
patch should be in firm contact with the patient's skin, preferably
forming a tight seal therewith. Drug within the patch will then
migrate through the patch to the patient's skin by diffusion. When
drug is in contact with the patient's skin, drug molecules which
are continuously being removed from the outer surface of the patch
migrate through, and are absorbed by, the skin, entering the
patient's circulation through the capillary network. The patch can
be applied to any area of the patient's skin, including the oral
mucosa, for example, by application of the patch to the patient's
palate or buccal mucosa. In addition, the patches of the invention
can be used to administer drugs to other mucosa of the body, for
example, by application to the vaginal mucosa, the rectal mucosa,
etc.
Patch Handling and Storage
The transdermal patches of the invention should be stored at
controlled room temperature, and should be protected from light.
Patches stored under cold conditions tend to show crystallization
on the surface. This is not observed for patches stored at room
temperature.
In order for an operator who is administering a transdermal patch
of the invention to a patient (physician, nurse, etc.) to avoid
unwanted exposure to an active drug ingredient dispersed throughout
the matrix of the patch, gloves should be worn when handling the
patch, and direct contact between the patch and the operator's skin
should be avoided.
While the various aspects of the transdermal patches of the present
invention are described herein with some particularity, those of
skill in the art will recognize numerous modifications and
variations which remain within the spirit of the invention. These
modifications and variations are within the scope of the invention
as described and claimed herein.
EXAMPLES
The examples presented below describe and illustrate the methods
for the preparation of the transdermal patches of the present
invention, as well as other aspects of the present invention, and
the results achieved thereby, in further detail. Both an
explanation of, and the actual procedures for, the various aspects
of the present invention are described where appropriate. These
examples are intended to be merely illustrative of the present
invention, and not limiting thereof in either scope or spirit.
Those of skill in the art will readily understand that known
variations of the conditions and processes of the preparative
procedures described in these examples can be used to prepare the
transdermal patches of the present invention.
All patents and publications referred to in the examples, and
throughout the specification, are hereby incorporated herein by
reference, without admission that such is prior art.
In the examples presented below, both single-layer (Examples 2 and
4) and double-layer (Example 3) albuterol patches of the invention
designed for once-a-day application were prepared.
In vitro and in vivo experiments were then conducted (Example I)
with both the single-layer and double-layer albuterol patches of
the present invention, prepared as described in Examples 2 and 3,
respectively, or prepared as otherwise described.
In the preliminary in vitro experiments (Examples 1(a), 1(b) and
1(c)), the in vitro drug release of single-layer (Example 2) and
double-layer (Example 3) transdermal patch formulations of the
invention were monitored via the permeation of albuterol from the
patches through hairless mouse skin (Example 1(a)) and monkey skin
(Example 1(c)), and via the dissolution of albuterol from the
patches in water (Example 1(b)).
The in vivo albuterol absorption, bioavailability, pharmacokinetics
and skin irritation were then monitored in Rhesus monkeys (Examples
1(e) and 1(f)). Intravenous albuterol pharmacokinetics was also
followed using a "crossover design" (a study in which the same
animals are used for each of the different in vivo experiments
performed, such as for the application of single-layer transdermal
albuterol patches, the application of double-layer transdermal
albuterol patches, and the intravenous administration of an
albuterol aqueous solution) in the same monkeys (Examples 1(d) and
1(f)).
In these in vivo experiments, at different times, single-layer and
double-layer albuterol patches of the invention, prepared as
described in Examples 2 and 3, respectively, were separately
applied to the chest area of four female Rhesus monkeys, designated
#388, #391, #423 and #430, and an albuterol aqueous solution was
separately injected into the saphenous vein of the same monkeys at
another time, in a "crossover design." Blood samples from the
monkeys were withdrawn at regular intervals after albuterol patch
application or injection and analyzed by an HPLC method. Skin
irritation of the monkeys was also measured by a Draize Score
Test.
Further in vivo skin irritation and sensitization tests were then
conducted with rabbits (Example 1(g)) and guinea pigs (Example
1(h)), respectively.
Finally, in vitro stability studies were conducted to study the
degradation of the transdermal albuterol patches of the invention
over time (Example 1(i)).
Each of the experiments described in examples 1(a)-(f) was
conducted several times with both single-layer and double-layer
transdermal albuterol patches of the invention. The number of times
a particular experiment was conducted is indicated in each example.
For example, (n=3) means that a particular experiment was conducted
three times.
Materials and Animals
Chemicals and solvents used in the experiments were obtained from
the following sources: nonmicronized albuterol from Co.
Pharmaceutica, Milanese, Italy; micronized albuterol from Labochim,
Milano, Italy; methanol, acetonitrile and chloroform from Burdick
Jackson, Muskegon, Mich.; water from Fisher Scientific Company,
Fairlawn, N.J.; Di (2-ethylhexyl) phosphate (DEHP), sodium
phosphate monobasic, sodium phosphate dibasic, bamethane sulfate,
glycerol, n-hexanol and n-dodecanol from Sigma Chemical Company,
St. Louis, Mo.; 1-pentane sulfonic acid sodium salt from Kodak,
Rochester, N.Y.; 0.9% sodium chloride irrigation solution from
Travenol Laboratories, Deerfield, Ill.; Silastomer.TM. X7-3058
elastomeric matrix material, X7-3059 crosslinking agent and X7-3075
catalyst from Dow Corning, Inc., Midland, Mich.; and triethylamine
from Aldrich Chemical Company, Inc., Milwaukee, Wis.
All solvents and chemicals were ACS analytical grade or HPLC
grade.
While nonmicronized albuterol was employed in Examples 1(a)-(f), 2
and 3, micronized albuterol was used in all of the other
examples.
The four female Rhesus monkeys used in the experiments described
hereinbelow (#388, #391, #423 and #430) were Macaca Mulata monkeys
which were obtained from the University of Texas in Austin,
Tex.
Generally, the computer programs referred to in the examples merely
provide a simpler and quicker means for obtaining the answers to
the mathematical equations specified or referred to therein.
SUMMARY OF EXAMPLES, TABLES AND FIGURES
The examples, tables and figures which correspond to the various
experiments described in the examples are as follows:
______________________________________ Correspon- Corre-
Corresponding ding sponding Subject Matter Example(s) Table(s)
FIG(S). ______________________________________ (1) Franz Cell
Example 1(a) Table I FIGS. 1 Experiments and 2 (2) Dissolution
Example 1(b) Table II FIG. 3 Experiments (3) Residue Example 1(c)
Table III None Analysis Experiments (4) Intravenous Example 1(d)
Tables IV FIG. 4 Administration and (f) and VI of Albuterol (5)
Patch Examples 1(e) Tables III, FIG. 4 Administration and (f) V,
VII, XI of Albuterol and XII (6) Comparison of Examples 1(a),
Tables I, II, None In Vitro Patch (b) and (c) III and IX Parameters
(7) Rhesus Monkey Examples 1(c), Tables VII None In Vitro- (d) and
(f) and VIII In Vivo Data Comparison (8) Hypothetical Example 1(f)
Tables X None Human Serum and XI Albuterol Concentrations (9)
Rabbit Skin Example 1(g) Tables XIII, None Irritation XIV and XV
Experiments (10) Guinea Pig Example 1(h) Tables XVI, None Skin XVII
and Sensitization XVIII Experiments (11) Patch Stability Example
1(i) Tables XIX, None Studies XX and XXI
______________________________________
EXAMPLE 1
Example 1(a)
In Vitro Franz Cell Experiments
(1) Albuterol Transdermal Patches
In these preliminary in vitro experiments, the in vitro albuterol
release of single-layer (Example 2) and double-layer (Example 3)
transdermal patch formulations of the invention were monitored via
the permeation of albuterol from the patches through hairless mouse
skin to determine whether or not albuterol would pass through the
mouse skin and, if so, the amount of albuterol which passed through
the mouse skin. These experiments were repeated several times using
both single-layer (n=3) and double-layer (n=6) transdermal
albuterol patches of the invention, prepared as described in
Examples 2 and 3, respectively.
An eight week old male hairless mouse (Nu/Nu CD-1, Charles River,
Bloomington, Mass.) was sacrificed by spinal dislocation, and then
a rectangular piece of abdominal skin tissue was carefully lifted
from the mouse and separated from the adhering fatty tissue and
visceral material.
The abdominal skin tissue was then mounted on a Franz Diffusion
Cell Assembly (Vanguard International, Neptune, N.J.) and clamped
between the donor and receptor compartments thereof, with the
epithelium portion of the skin tissue facing the donor
compartment.
The temperature of the receptor compartment of the Franz Diffusion
Cell Assembly was maintained by an external constant temperature
water bath set at 37.degree. C. A receptor solution (7 mL of normal
saline solution) present in the receptor compartment was stirred
with a magnetic stirrer to bath the dermis of the mouse skin
tissue, thereby removing the adhering cell debris.
After two hours of this bathing, the receptor solution was
withdrawn and replaced with 7 mL of fresh saline solution, which
had been previously equilibrated at 37.degree. C.
Following this, an approximately 1.38 square centimeter transdermal
patch of the invention, prepared as described in Example 2
(single-layer) or 3 (double-layer), was applied to the epidermal
side of the mouse skin tissue, which was facing the donor
compartment of the Franz Diffusion Cell Assembly, and the foil was
removed from the patch.
After a period of 24 hours, a 300 microliter sample of the receptor
solution was then removed from the sampling port of the apparatus
and filtered. The albuterol concentration of the receptor solution
sample was then determined by the High Performance Liquid
Chromatography Method (HPLC) described below.
The HPLC system consisted of a 25 cm.times.4.6 mm Zorbax CN column
(Zorbax, Dupont, Wilmington, Del.) and a mobile phase consisting of
5% acetonitrile and 95% water with 0.005 M pentane sulfonic acid,
pH 2.5, low UV (v/v). The column temperature was ambient, and the
mobile phase was pumped at a flow rate of I.0 mL/minute. The
detector was a Kratos SF 770 detector (Kratos Analytical
Instruments, Ramsey, N.J.). Other parameters were as follows: chart
speed, 0.5 cm/minute; wavelength, 200 nm; sensitivity, 0.6 AUFS;
run time, 10 minutes; and injection volume, 40 .mu.L.
The resulting chromatographic peak height was quantitated using the
Ingrad Data Analysis System (G. D. Searle & Co., Skokie, Ill.),
and compared with the standard calibration curve, to determine the
unknown concentration of albuterol in the receptor solution sample.
However, chromatographic peak heights may be calculated by other
methods known by those of ordinary skill in the art.
The albuterol concentration obtained from the HPLC analysis was
then converted into an amount (that amount of albuterol which was
released from the transdermal albuterol patch in the donor
compartment of the assembly and which passed across the mouse skin
into the receptor solution contained in the receptor compartment of
the assembly), by the following formula: ##EQU2##
Once these experiments were performed three times each (n=3) for
the single-layer, and six times each (n=6) for the double-layer,
transdermal albuterol patches of the invention, the amounts were
then normalized (adjusted to a 1 square centimeter patch by
dividing the amount of albuterol calculated by the exact size of
the patch actually cut) for the exposed surface area of the
transdermal albuterol patch (approximately 1.38 square centimeters)
to calculate the in vitro hairless mouse "skin permeation rate
constant" (in vitro "release rate constant") (mg.cm.sup.-2
day.sup.-1).
The resulting "skin permeation rate constant" values obtained were
then averaged separately for the single-layer (n=3) and double
layer (n=6) patches to determine the mean (average) "skin
permeation rate constant." These values are presented in Table
I.
The mean hairless mouse "skin permeation rate constant" indicates
the average amount of albuterol (in milligrams) which was released
from a 1 square centimeter transdermal albuterol patch across a 1
square centimeter portion of skin of a hairless mouse during a
period of twenty-four hours (mq.cm.sup.- 2.day.sup.-1). It is a
transdermal drug delivery patch parameter which is a
characterization of the particular patch, and which can be compared
to the same parameter of other transdermal patches to compare the
ability of the various patches to deliver a particular active
agent.
Skin permeation of albuterol incorporated into the patches was a
function of the dissolution of albuterol in the Dow X7-3058
Silastomer.TM. elastomeric matrix material, and albuterol
solubility and diffusivity in the hairless mouse skin membranes,
especially the stratum corneum.
(2) Albuterol Solutions
(a) Different Adjuvant Agents
In order to determine the affect of various adjuvant agents
[ethanol (EtOH), Azone, and isopropyl alcohol (IPA)] on the flux of
albuterol through the skin of a hairless mouse, the same
experiments described above in Example 1(a)(I) were conducted, with
the exceptions that: (1) rather than applying a transdermal
albuterol patch to the epidermal side of the mouse skin tissue,
approximately 3 mL of an albuterol solution consisting of
approximately 10 mg of albuterol per mL of normal saline solution
(NEAT I) with or without 50 mg/mL of adjuvant agent was added to
the donor compartment of the Franz Diffusion Cell Assembly; (2) a
300 microliter sample was removed from the receptor compartment of
the assembly (and replaced with the equivalent volume of normal
saline solution) periodically over a period of 2, 5, 7 and 24
hours; and (3) the amounts of albuterol calculated were corrected
for the dilution factor (because the original volume of receptor
solution (7 mL) was diluted every time an additional 300
microliters of normal saline solution was added) by methods known
by those of skill in the art.
The results of these experiments are presented in FIG. 1, and show
that ethanol was the most effective adjuvant agent tested.
(b) Different Hydrocarbon Alcohols
In order to determine the affect of various normal hydrocarbon
alcohols [dodecanol, nonyl alcohol, hexanol, n-propanol, decanol,
and ethanol (EtOH)] on the flux of albuterol through the skin of a
hairless mouse, these experiments were conducted again, as
described in Example 1(a)(2)(a), but using these different normal
hydrocarbon alcohols.
The results of these experiments are presented in FIG. 2, and show
that, generally, the effect of the alcohol on albuterol flux
increases as the chain length of the alcohol increases.
Example 1(b)
In Vitro Dissolution Experiments
In these preliminary in vitro experiments, the in vitro drug
release of single-layer (Example 2) and double-layer (Example 3)
transdermal patch formulations of the invention were also
monitored, but via the dissolution of albuterol from the patches in
water.
An approximately 8 square centimeter albuterol transdermal patch,
prepared as described in Example 2 (single-layer) or 3
(double-layer), was mounted on the L holder of a Hanson's
Dissolution Test Apparatus Model 72 RL (Hanson Research,
Northridge, Calif.). The holder of the apparatus was composed of a
stainless steel rod fitted with a circular disc and a metal screw
cap. The screw cap had a 4 square centimeter open circular area in
the center which was exposed to a dissolution medium consisting of
300 mL of water at 37.degree. C. being stirred at 50 rpm.
5 mL samples of the dissolution medium were removed from the
sampling port of the apparatus at periodic time intervals following
the mounting of the patch on the apparatus (2, 5, 7 and 24 hours)
for a period of twenty-four hours. Each volume of sample removed
was replaced with mL of water to keep the amount of dissolution
medium constant.
The albuterol concentration of each of these 5 mL samples was then
determined by the method similar to that described in Example
1(a).
The albuterol concentrations were then converted into amounts in
the manner similar to that described in Example 1(a) and corrected
for the dilution factor, which was the volume of the dissolution
medium (300 mL), also in the manner described in Example 1(a).
Once these experiments were performed three times each (n=3) for
the single-layer, and six times each (n=6) for the double-layer,
transdermal albuterol patches, the amounts calculated for those
samples of dissolution medium removed from the Hanson's apparatus
after 24 hours were normalized in the manner described in Example
1(a)(l) for the exposed surface area of the albuterol patches
(approximately 4 square centimeters) to calculate the in vitro
"dissolution rate constant" (mg.cm.sup.-2.day.sup.-1).
The resulting "dissolution rate constant" values obtained were then
averaged separately for the single-layer (n=3) and double-layer
(n=6) patches to determine the mean "dissolution rate constant."
These values are presented in Table II.
The "dissolution rate constant" indicates the average amount of
albuterol (in milligrams) which was released from a 1 square
centimeter transdermal albuterol patch into the dissolution medium
during a period of twenty-four hours (mg.cm.sup.-2.day.sup.-1).
This is also transdermal drug delivery patch parameter which is a
characterization of the particular patch, and which can be compared
to the same parameter of other transdermal patches to compare the
ability of the various patches to deliver a particular active
agent. It is also used to predict the amount of active agent which
will be released from a I square centimeter patch into the serum of
a patient during a twenty-four hour period, and should correlate
with the data obtained from in vivo experiments employing the same
patches.
The time course of albuterol concentrations following patch
dissolution in the Hanson's Dissolution Test Apparatus is shown in
FIG. 3. This plot of drug release versus time was nonlinear and
biphasic, showing a burst effect (rapid drug depletion in the
initial phase). The magnitude of the burst effect was higher in the
single-layer than in the double-layer patch. However, the amount of
albuterol dissolved in the dissolution medium at 24 hours was
similar in both patches (Table II).
Dissolution of albuterol from the patches into the dissolution
medium was a function of the solubility of the drug, its
diffusivity in the Dow X7-3058 Silastomer.TM. elastomeric matrix
material, the solubility and diffusivity of albuterol in water, and
the resistance of the aqueous diffusion layer of the patches.
Example 1(c)
In Vitro Patch Residue Analysis Experiments
In these experiments, the albuterol release of single-layer
(Example 2) (n=4) and double-layer (Example 3) (n=3) transdermal
patch formulations of the invention were monitored via the
permeation of albuterol from the patches through Rhesus monkey skin
to determine whether or not albuterol would pass from the patch
formulations through the monkey skin and, if so, the amount of
albuterol which passed through the monkey skin.
After overnight fasting, each of Rhesus monkeys #388, #391, #423
and #430 was restrained in a chair, and then its chest area was
clipped to remove hair. Chest skin surfaces were then wiped clean
with an isopropyl alcohol solution.
An approximately 4 square centimeter transdermal patch of the
invention, prepared as described in Example 2 (single-layer) or 3
(double-layer) was then applied to the chest area of each Rhesus
monkey in the manner described in Example 1(a), pressing gently for
proper adhesion. (While single-layer patches were applied to each
of the four monkeys, double-layer patches were only applied to
Rhesus monkeys #388, #391 and #423. Only one patch was applied to a
monkey per experiment.)
The initial albuterol content in each patch had been estimated from
the weight of the patch, the "content uniformity" (a value obtained
by determining the average amount of albuterol extracted from
similar-sized patches in the manner described below), and the
"percent loading" (the percent of albuterol initially incorporated
into the patch).
After 24 hours, the transdermal patch was carefully removed from
each monkey, and then separated from its adhesive backing.
The residual content of albuterol in each patch was then determined
by extracting the patch with 30 mL of acetone for a period of
twenty-four hours, and then analyzing the extracts by the HPLC
method described above in Example 1(a). From the initial and
residual albuterol content in the patch, the loss of albuterol from
the patch (absorbed amount) and, hence, the Rhesus monkey "skin
permeation rate constant" (in vitro "release rate constant" of
albuterol from the patch) in milligrams per square centimeter per
day (mg.cm.sup.-2.day.sup.-1) was calculated in the following
manner: ##EQU3##
The mean values and standard deviations are presented in Table
III.
In conclusion of Examples 1(a)-(c), the amount of albuterol
released from the patches of the invention was dependent on the in
vitro technique used, and decreased in the following manner: pad
dissolution>monkey skin permeation>hairless mouse skin
permeation. The in vitro "dissolution rates" from the patches
(Example 1(b) and Table II) were faster than the "skin permeation
rates" in hairless mouse (Example 1(a) and Table I) and Rhesus
monkey (Example 1(c) and Table III). The hairless mouse "skin
permeation rates" were somewhat lower, but comparable to the Rhesus
monkey "skin permeation rates."
As shown in Tables I and II, the "dissolution rates" and hairless
mouse "skin permeation rates" of the single-layer and double-layer
albuterol patches were similar. However, as shown in Table III, the
value of the Rhesus monkey "skin permeation rate constant" for a
double-layer patch was higher than that for a single-layer
patch.
In the double-layer patch experiment, albuterol content was
monitored only in the layer of the patch which contained albuterol.
It was not monitored in the layer which contained other formulation
components. It is suspected that albuterol had migrated into the
n-dodecanol layer, as it did into the skin membrane, thereby
depleting the drug layer at a faster rate.
Example 1 (d)
"Intravenous Administration" of Albuterol to Rhesus Monkeys
Rhesus monkeys #388, #391, #423, and #430 were employed in a
"crossover design" for the albuterol intravenous administration and
transdermal patch administration bioavailability experiments
described in Examples 1(d)-(f).
From each monkey, a 7 mL blood sample was removed on the day
previous to the day of the albuterol intravenous administration
bioavailability experiment, and then centrifuged to obtain the
serum. The serum was then stored at -20.degree. C. until the
analysis described in Example 1(f)(1) was performed. These serum
samples were used to make blanks and standards (controls).
Following this, the monkeys were fasted overnight, restrained and
settled in chairs before receiving an intravenous injection of
albuterol.
An albuterol solution containing 50 mcg of albuterol per mL of 0.9%
sodium chloride was prepared. This solution was injected into the
saphenous vein of each monkey at a dose of 1 mL/Kg of
bodyweight.
A 5 mL blood sample was then taken from each monkey at 0.00, 0.08,
0.17, 0.33, 0.75, 1.00, 1.5, 2.00, 3.00, 4.00, and 5.00 hours
following the albuterol injection. The serum from each blood sample
was separated from other blood components via centrifugation, and
then stored at -20.degree. C. until the analysis described in
Example 1(f)(1) was performed.
Example 1(e)
"Transdermal Patch Administration" of Albuterol to Rhesus
Monkeys
After overnight fasting, on the day of the albuterol transdermal
patch administration for the bioavailability experiment, the same
four Rhesus monkeys described in Example 1(d) above (#388, #391,
#423 and #430) were restrained in chairs, and then their chest
areas were clipped to remove hair, avoiding any injury to the skin
tissue. Chest skin surfaces were wiped with an isopropyl alcohol
swab, and then an approximately 4 square centimeter albuterol
transdermal patch of the invention, prepared as described in
Example 2 (single-layer) or 3 (double-layer), was applied to the
chest area of each monkey in the manner described in Example 1(a)
for a period of 24 hours, after which it was removed in the manner
described in Example 1(c). (While single-layer patches were applied
to each of the four monkeys, double-layer patches were only applied
to Rhesus monkeys #388, #391 and #423. Only one patch was applied
to a monkey per experiment.)
A 5 mL blood sample was taken from each monkey at 0.00, 0.5, 1.00,
1.50, 3.00, 5.00, 7.00, 12.00, 24.00, 31.00, and 48.00 hours post
transdermal albuterol patch application, centrifuged to obtain the
serum, and then stored at -20.degree. C. until the analysis
described in Example 1(f)(2) was performed.
Monkey skin irritation was evaluated 24 hours post patch
application by a Draize Score technique, as described by J. H.
Draize, Assoc. Food Drug Off., 46-47 (1959). The maximum possible
score in this test is 4, indicating maximum skin irritation.
The scores obtained from this modified Draize Score technique were
0 or 1 for each of the four monkeys tested, indicating little or no
skin irritation from the transdermal albuterol patches of the
invention.
Moreover, no adverse skin reactions or sensitizations were seen
when the monkeys were monitored for 7 days post patch
application.
Example 1 (f)
Analysis of Serum Samples from the Albuterol "Intravenous
Administration" and "Transdermal Patch Administration"
Experiments
Serum albuterol and bamethane sulphate, which was employed as an
internal standard, were extracted from each of the serum samples
described in Examples 1(d) and (e) into chloroform to remove polar
interfering substances, and were then reextracted into the aqueous
phase of the initial extraction to eliminate nonpolar materials, in
the manner described directly below.
In separate clean test tubes, 1.5 mL of serum standard (Example
1(d)), serum sample (Examples 1(d) and (e)) and blank (Example
1(d)) was separately buffered with 150 microliters of a 0.42 M
phosphate buffer, pH 7.2.
Each serum sample was then extracted with 4.5 mL of chloroform
containing 0.1 M Di (2-ethylhexyl) phosphate (DEHP). The chloroform
layer was separated into clean screw cap test tubes and mixed with
375 microliters of a 0.5 M HCl solution.
The aqueous extracts were then separated by centrifugation and
analyzed by the HPLC-Fluorescence procedure described directly
below.
The HPLC system consisted of a Waters Model 590 (Millipore
Corporation, Bedford, Mass.) solvent delivery system equipped with
a Waters Model 710 B Wisp auto injector, a Zorbax CN column
(Dupont, 6 micron particles, 25 cm.times.4.6 mm internal diameter),
Kratos (Kratos Analytical Instruments) Model 970 fluorescence
detector (excitation 225 nm and emission 280 nm), and the Ingrad
Data Analysis system (G. D. Searle & Co.). The mobile phase
consisted of a mixture of 6 parts methanol in 94 parts aqueous
solution of 0.005 M pentane sulfonic acid (pH 2.5). The mobile
phase was pumped at a flow rate of 1.0 mL/minute. The injection
volume was 100 microliters. The sensitivity of the method was 2.0
ng/mL.
The resulting chromatographic peak heights were quantitated using
the Ingrad Data Analysis system, and compared with the standard
calibration curve, to determine the unknown concentration of
albuterol in each of the serum samples. However, chromatographic
peak heights may be calculated by other methods known by those of
ordinary skill in the art.
The standard calibration curve was linear over the concentration
range of 2.5 to 200 ng/mL, as evidenced by the correlation
coefficient of better than 0.99. The coefficient of variation
associated with low (10 ng/mL) and high (80 ng/mL) quality control
standard solutions were 4.5 and 3.4 percent, respectively.
Pharmacokinetic parameters were then estimated as described
directly below, by conventional pharmacokinetic methods well known
to those of ordinary skill in the art, and described by M. Gibaldi
et al., Pharmacokinetics (New York 1975).
(1) Data Analysis of Serum Concentration Versus Time Profiles after
"Intravenous Administration" of Albuterol
Serum albuterol concentration time data obtained after albuterol
"intravenous administration" are presented in Table IV, and were
fitted to a two-compartment open model using `C strip` and `Nonlin`
statistical computer programs, as described by J. G. Wagner, J.
Pharm. Sci. 65, 1006-1010 (1976) and C. M. Metzler, Research
Biostatistics, The Upjohn Co., Kalamazoo, Mich. (1974).
Model parameters were calculated using conventional pharmacokinetic
equations, as described by M. Gibaldi et al., supra.
As can be seen in Table IV and FIG. 4, albuterol concentrations
after "intravenous administration" declined biexponentially. (The
initial portion of each of the curves in FIG. 4 was attributed to
the distribution of albuterol to different tissues, and the
terminal portion of the curves was attributed to the removal of
albuterol via elimination processes.)
The mean pharmacokinetic parameters obtained via the `Nonlin`
program are shown in Table VI. The mean "initial half life" (the
amount of time it took for 50% of the albuterol to get distributed
into different body compartments) obtained was 6.0 minutes. The
mean "terminal half-life" (the amount of time it took for 50% of
the albuterol to be eliminated from the body), "clearance" (Cl)
[rate of elimination of albuterol from the body (in milliliters of
"apparent volume of distribution" per minute per kilogram of body
weight (mL.minute.sup.-1 Kg.sup.-1)), as described by M. Gibaldi et
al., supra.], and "apparent volume of distribution" (a measure
which indicates the extent of the distribution of albuterol in the
body) obtained from the serum concentration time data (Table IV and
FIG. 4) following the 50 mcg/mL intravenous injection of albuterol
were 135.6.+-.26.93 minutes, 10.2.+-.1.8
mL.minute.sup.-1.Kg.sup.-1, and 1935.9.+-.37.2 mL.Kg.sup.-1,
respectively.
The mean "terminal half-life" in monkeys is comparable to that in
man, which ranges from 3 to 6 hours (from 180 to 360 minutes). The
"clearance" value in monkeys agrees reasonably well with the
previously-reported values of 6-8 mL.minute.sup.-1.Kg.sup.-1 in
humans. Moreover, the "apparent volume of distribution" in humans
is 2200 mL.Kg.sup.-1, which is similar to that in monkeys.
In summary, the pharmacokinetic parameters determined for the
Rhesus monkeys are similar to those reported for humans.
(2) Serum Analysis after "Transdermal Patch Administration" of
Albuterol
The serum albuterol concentration time data obtained after the
single-layer (Example 2) and double-layer (Example 3) albuterol
transdermal patch application described in Example 1(e) to the four
Rhesus monkeys is presented in Table V (single-layer) and Table XII
(double-layer), and in FIG. 4.
Pharmacokinetic parameters were then estimated in the manner
described directly below, and the mean values are presented in
Table VII.
Following patch application, there was lag time (t.sub.L) of
approximately 3 hours before albuterol concentrations could be
detected in the serum (FIG. 4). The time course release of
albuterol administered transdermally through a patch of the
invention showed a steady incline in each of the four monkeys
tested up to 12 hours following the patch application. Thereafter,
the "steady-state" serum albuterol concentrations (C.sub.ss) (the
concentration of albuterol remaining essentially the same over
time, so that a plot of time versus albuterol concentration would
show a horizontal plateau, due to the equilibrium reached between
the rate of albuterol absorption and the rate of albuterol
elimination from the body) were maintained until the transdermal
patch was removed at 24 hours. As shown in FIG. 4 and Tables V and
XII, serum drug levels were sustained for the 24-hour period,
reaching steady state sometime between 12 and 24 hours. In all of
the monkeys tested, albuterol concentrations declined rapidly after
the patch was removed, with no measurable albuterol concentration
remaining at 48 hours.
The albuterol "steady-state concentrations" (Css) in nanograms of
albuterol per mL of serum (ng.mL.sup.-1) after transdermal patch
administration were calculated by averaging the mean 12- and
24-hour drug concentrations in serum.
In vivo "absorption rate constants" (K.sub.O) in milligrams of
albuterol absorbed from a 1 square centimeter patch over a period
of twenty-four hours (mg.cm.sup.- 2 day.sup.- 1) were then
calculated assuming an intravenous infusion-like input and using
the formula:
where Cl is the "clearance" (rate of elimination of the drug from
the body), and is calculated in the manner described by M. Gibaldi
et al., supra. These values are presented in Table VII.
"Area under the curve" (AUC) values [values of the amount of
albuterol in the serum at a given point in time
(ng.mL.sup.-1.hours)] were then calculated using the standard
trapezoidal rule and the following mathematical formula, as
described by M. Gibaldi et al. at Page 447: ##EQU4## where C.sub.1
represents the first concentration, C.sub.2 represents the second
concentration, T.sub.1 represents the first time and t.sub.2
represents the second time, as shown in FIG. 5.
The resulting AUC values were then used to calculate the
"bioavailability" (F) of albuterol administered transdermally
through a single-layer or double-layer patch of the invention.
These values are presented in Table VII.
The "skin bioavailability" (F) of albuterol administered
transdermally through a single-layer or double-layer transdermal
patch was calculated using the following mathematical equation, and
using the dose and area under the curve (AUC) values obtained
following the intravenous or transdermal administration of
albuterol which are presented in Table XI: ##EQU5## where, TR and
IV represent transdermal and intravenous administration,
respectively, and Dose represents the dose of albuterol given to
the Rhesus monkey, either intravenously (50 mcg of albuterol per Kg
of body weight) or transdermally. The "transdermal dose" was
determined from the Rhesus monkey "skin permeation rate constant"
("in vitro release rate constant") presented in Table III. [The
"transdermal dose" is equal to the Rhesus monkey "skin permeation
rate constant" ("in vitro release rate constant")].
The "skin bioavailability" (F) of single-layer patches was
calculated to be 115.0.+-.16 percent (Table VII). (The "skin
bioavailability" (F) of the double-layer patches was not
calculated.) This shows that, unlike the oral administration of
albuterol, albuterol administered transdermally through a patch of
the invention did not undergo a substantial first pass metabolism,
and was 100% bioavailable. In addition, the patches maintained
sustained serum drug levels of albuterol for a 24-hour period, with
insignificant skin irritation.
The in vivo "absorption rate constant" calculated for the
double-layer patch was higher than that calculated for the
single-layer patch (Table VII). However, this difference was
statistically insignificant [p<0.05, based on the student's
t-test (a statistical test employed to determine the difference
between 2 means, which is known by those of skill in the art)].
The single-layer and double-layer transdermal albuterol patch
formulations were bioequivalent in that their "steady-state
concentration" (C.sub.ss), in vivo "absorption rate constant"
(K.sub.O) and "area under the curve" (AUC) values (Table VII) were
not statistically different (p<0.05, based on the student's
t-test).
(3) Comparison of In Vitro and In Vivo Data
A summary of the in vitro parameters of the albuterol patches of
the invention is presented in Table IX. The hairless mouse "skin
permeation rate constants," in vitro "dissolution rate constants"
and Rhesus monkey "skin permeation rate constants" were obtained
from Tables I, II and III, respectively.
The in vitro Rhesus monkey "skin permeation rate constants" (in
vitro "release rate constants") determined in Example l(c) (Table
III) were then compared with the in vivo Rhesus monkey "absorption
rate constants" (K.sub.O) calculated in Example 1(f)(2) (Table VII)
to determine whether or not the Rhesus monkey in vitro data
correlated with the Rhesus monkey in vivo data. These numbers are
presented in Table VIII.
As can be seen in Table VIII, the in vitro Rhesus monkey "skin
permeation rate constant" shows approximately a 1:1 correlation
with the corresponding Rhesus monkey in vivo "absorption rate
constant."
(4) Hypothetical Human Serum Albuterol Concentrations
The transdermal albuterol dose calculated in Example I(f)(2) (Table
XI) was extrapolated from a 5-Kg Rhesus monkey to a 70-Kg human to
predict the human serum albuterol concentrations shown in Table X.
Assuming that the "clearance" (Cl) and in vivo "absorption rate
constants" (K.sub.O) for albuterol administered transdermally to
monkeys are the same as those for humans, these values were used to
predict albuterol concentration in a hypothetical 70-Kg human.
As shown in Table X, hypothetical albuterol serum concentrations
were in the range of 8-10 ng/mL following applications of an 8
square centimeter single- or double-layer transdermal albuterol
patch. These values compare reasonably well with those (11.0 and
11.1 ng/mL) obtained from the four-times-a-day instant release (IR)
(4 mg) and the two-times-a-day controlled release (CR) (8 mg)
albuterol sulphate tablet formulations in humans, as reported by R.
S. Sykes et al., Biopharm Drug Dispo., 9, 551-556 (1988) and M. L.
Powell et al., J. Clin. Pharmacol. 26, 643-646 (1986).
Moreover, due to the increased bioavailability associated with the
transdermal albuterol patches of the invention (6 mg of albuterol
permeated from an 8 square centimeter patch), equivalent serum
concentrations can be achieved with transdermal albuterol patches
containing albuterol amounts of approximately 40 percent of that of
the oral dose [16 mg total from either an instant-release (IR)
tablet (4 mg of albuterol 4 times per day) or a controlled-release
(CR) tablet (8 mg of albuterol 2 times per day)].
In patients, the once-a-day application of a transdermal albuterol
patch of the invention should provide a similar therapeutic effect.
This would also reduce the "Cmax value" (the maximum concentration
of albuterol in the serum during a given period of time) in the
serum, thereby minimizing side effects.
Example 1(g)
Rabbit Skin Irritation Tests
Rabbit skin irritation experiments were conducted in order to
assess the potential irritant and/or corrosive effects of the
transdermal albuterol patches of the invention on the skin of
rabbits. The rabbit was the system of choice because rabbits have
been used historically for this type of study. Thus, the data
generated from this study could be compared to that generated from
rabbits for other topical preparations.
Six young adult New Zealand White Rabbits, designated #7658/Male,
#7661/Male, #7708/Female, #7687/Female, #7689/Female and
#7692/Male, were obtained from a SLS and USDA approved supplier.
The animals were maintained under standard laboratory conditions
adhering to AAALAC standards. Animals were acclimatized for a
minimum of five days prior to dosing.
On the day prior to dosing, the fur was clipped from the dorsal
area of the trunk of each rabbit, using a small animal clipper.
On the day of dosing, a transdermal albuterol patch of the
invention, prepared as described in Example 4 (single-layer), was
applied to a small area of the exposed skin on two of the rabbits,
and held in place with nonirritating tape. A stockinette sleeve was
placed over the trunk of the two rabbits and secured at both ends
with tape to prevent the removal and ingestion of the patches.
The rabbits were observed for pharmacological signs of toxicity at
one and three hours both post patch application and prior to patch
removal (approximately 24 hours post patch application). Following
the 24-hour exposure period, there were no significant signs of
toxicity to the two rabbits. Thus, the remaining four rabbits were
dosed with a test patch in a similar manner.
The test patch was also removed from these four rabbits at 24 hours
post patch application. The rabbit test site on each of the six
rabbits was examined for signs of erythema and edema at scoring
intervals of 24 and 72 hours post patch removal according to the
dermal irritation grading system presented in Table XIII. If there
was no evidence of dermal irritation at the 72-hour scoring
interval, the study was terminated. If dermal irritation persisted
at any test site, the observation period was extended for the
affected animals (scored on day 7). Animals requiring an extended
observation period remained on test until the irritation was
resolved or permanent injury was evident.
The 24-hour, 72-hour and 7-day erythema and edema scores obtained
for the six rabbits according to the dermal irritation system
presented in Table XIII are presented in Table XV.
The 24- and 72-hour erythema and edema scores for each of the six
rabbits were then added together, and the resulting total was
divided by 12 (2.times.6 rabbits) to yield the mean Primary
Irritation Index (P.I.I.). The mean P.I.I. was calculated to be
2.83, and was classified according to the standard evaluation
criteria presented in Table XIV.
Example 1(h)
Guinea Pig Skin Sensitization Tests
Guinea pig skin sensitization tests were conducted in order to
assess the potential of the transdermal albuterol patches of the
invention to elicit a delayed contact hypersensitivity response
(adverse skin reaction) in guinea pigs after multiple, separate
applications of the patches to the guinea pigs. The guinea pig was
the system of choice because guinea pigs have been used
historically for this type of a study. Thus, the data generated
from this study could be compared to that generated from guinea
pigs for other topical preparations.
All transdermal albuterol patches of the invention employed in
these experiments were prepared in the manner described in Example
4 (single-layer), were circular in shape and were approximately 1
centimeter in diameter.
Twenty-seven male Harley derived guinea pigs were obtained from an
SLS and USDA approved supplier. The guinea pigs were maintained
under the standard laboratory conditions adhering to the AAALAC
standards, and were acclimatized for a minimum of five days prior
to dosing.
Two guinea pigs were assigned to "Dermal Dose Range Finding
Studies." Fifteen guinea pigs were assigned to "Dermal
Sensitization Induction Studies," followed by "Dermal Sensitization
Challenge Studies," followed by "Dermal Sensitization Rechallenge
Studies." Five control guinea pigs were assigned to the "Dermal
Sensitization Challenge Studies," and five control guinea pigs were
assigned to the "Dermal Sensitization Rechallenge Studies."
(1) Dermal Dose Range Finding Studies
On the day prior to the dosing, the hair was clipped from the
dorsal trunk area of the two guinea pigs designated for this study
using a small animal clipper.
On the following day, one transdermal albuterol patch was applied
to the exposed skin of each animal. Following this, a sheet of
rubber dental dam was pulled taut over the dorsal trunk of each
animal to completely occlude the test site.
Approximately six hours after dosing, the dental dam and patches
were removed from each animal. The test sites were wiped with gauze
moistened with distilled water, and the animals were returned to
their individual cages.
Approximately twenty hours later, residual hair was removed from
the exposure site on each guinea pig using a commercial depilatory.
The depilatory was applied directly to the test sites and
surrounding skin on each animal. Within 15 minutes, the depilatory
was removed using warm running water and the animals were blotted
dry using paper towels. A minimum of two hours after depilation,
the test sites were graded for irritation according to the
following scale:
Scoring Method
0=No Reaction
.+-.=Slight, Patchy Erythema
1=Slight, but Confluent or Moderate, Patchy Erythema
2=Moderate Confluent Erythema
3=Severe Erythema with or without Edema
Results of the "Dermal Dose Range Finding Studies" are presented in
Table XVI. Dermal reaction in the two guinea pigs was limited to 0
and .+-. Scores. Thus, the patches were acceptable for the
subsequent studies.
(2) Dermal Sensitization Induction Studies
On the day prior to dosing, the hair was clipped from the left
flank area of each of the fifteen guinea pigs designated for these
experiments, using a small animal clipper.
On the following day, one transdermal albuterol patch was applied
to the exposed skin of each animal. Following this, a sheet of
rubber dental dam was pulled taut over the left flank area of each
animal to completely occlude the test sites.
Approximately six hours after dosing, the dental dam and patches
were removed from each animal. The test sites were wiped with gauze
moistened with distilled water, and the animals were returned to
their individual cages.
The induction procedure was repeated for each test animal three
times per week, until a total of nine induction applications had
been made.
Following each induction procedure, test sites were scored 24- and
48-hours postdose for dermal irritation using the scoring method
described above.
Following the final induction procedure, the guinea pigs were left
untreated for a period of 14 days.
Results of the "Dermal Sensitization Induction Studies" are
presented in Table XVII. Dermal reaction in the guinea pigs was
limited to 0 and .+-. scores.
(3) Dermal Sensitization Challenge Studies
On the day prior to the Dermal Sensitization Challenge Studies, the
hair was clipped from the posterior left flank area of the fifteen
test guinea pigs, and from the five control guinea pigs, designated
for these experiments using a small animal clipper.
On the following day, one transdermal albuterol patch was applied
to the exposed virgin skin of each animal. Following this, a sheet
of rubber dental dam was pulled taut over the posterior left flank
area of each animal to completely occlude the test sites.
Approximately six hours after dosing, the dental dam and patches
were removed from each animal. The test sites were wiped with gauze
moistened with distilled water and the animals were returned to
their individual cages.
Approximately twenty hours later, residual hair was removed from
the exposure site on each animal using the commercial depilatory
described above. The depilatory was applied directly to the test
sites and surrounding skin on each animal. Within 15 minutes the
depilatory was removed using warm running water, and the animals
were blotted dry using paper towels. A minimum of two hours after
depilation, the test sites were graded for irritation according to
the scoring method described above.
Results of the "Dermal Sensitization Challenge Studies" are
presented in Table XVIII. Dermal reaction in the guinea pigs was
limited to 0 and .+-. Scores. Dermal reaction in control animals
was limited to 0 scores.
(4) Dermal Sensitization Rechallenge Studies
Dermal Sensitization Rechallenge Studies were not conducted,
because they were determined not to be necessary.
From these experiments, it was concluded that the transdermal
albuterol patches of the invention are not contact sensitizers (do
not cause adverse skin reaction as a result of multiple separate
applications of the patches) in guinea pigs.
Example 1(i)
Transdermal Albuterol Patch Stability Studies
Stability studies were conducted to study the degradation of the
transdermal albuterol patches of the invention at different
temperatures (30.degree. C., 45.degree. C. and 55.degree. C.) over
a period of time (20 and/or 12 weeks) and, thus, to estimate the
shelf lives of these patches.
The content of albuterol in several transdermal albuterol patches
of the invention, which were prepared in the manner described in
Example 4 (single-layer), was analyzed over a period of several
weeks (20 and 12) as a function of loss of albuterol from the
patches over time, which was calculated in the manner described in
Example 1(c).
(1) Stability Study at 30.degree. C.
Transdermal albuterol patches of the invention were separately
wrapped in aluminum foil, and then placed in a sachet which was
lined with polyethylene. The sachet was placed in a 30.degree. C.
oven. At periodic intervals over a period of 20 weeks, sample
patches were removed from the oven, and then removed from the
sachet and the aluminum foils.
The patches were then analyzed by the HPLC procedure described in
Example 1(a).
The results of these experiments showed a 95 to 100 percent
recovery of albuterol from patch samples stored at 30.degree. C.
during the period of 20 weeks. Thus, the transdermal albuterol
patches of the invention were stable at 30.degree. C. for the
20-week period.
(2) Stability Studies at 45.degree. C. and 55.degree. C.
Further stability studies were conducted at 45.degree. C. and
55.degree. C. in the manner described directly above, with the
exceptions that: (a) 45.degree. C. and 55.degree. C.
controlled-temperature cabinets were used in place of the oven; (b)
patch samples were analyzed over a 12-week period according to the
schedule presented below, where "Patch Analysis" indicates that 3
patches were removed from the controlled-temperature cabinet at the
corresponding time and analyzed; and (c) a different HPLC method
was used.
______________________________________ Time 45.degree. C.
Experiments 55.degree. C. Experiments
______________________________________ 0 Weeks Patch Analysis Patch
Analysis 2 Weeks -- Patch Analysis 3 Weeks Patch Analysis -- 4
Weeks -- -- 6 Weeks Patch Analysis Patch Analysis 9 Weeks Patch
Analysis -- 12 Weeks Patch Analysis Patch Analysis
______________________________________
After the sample patches were removed from the 45.degree. C. and
55.degree. C. controlled-temperature cabinets, and then separated
from the sachet and the aluminum foils, they were then subjected to
HPLC analysis using the HPLC system described directly below.
This HPLC system consisted of an Altex Ultrasphere ODS, C18 (25
cm.times.4.6 mm i.d.) 5 micron column (Altex Corporation, CA), and
a mobile phase consisting of I% triethylamine (TEA)
buffer:methanol:acetonitrile (89:7:4). The column temperature was
ambient, and the mobile phase was pumped at a flow rate of 1.0 mL
per minute. Other parameters were as follows: detection, UV 210 nm
at 0.2 AUFS; run time, 45 minutes; injection volume, 100 mcL; and
sample concentration, 40 mcg/mL.
Results of the individual stability studies (per cent recovery of
albuterol from patch samples, determined in the manner described
above, and in the manner described in Example 1(c)) are presented
in Tables XX (stability studies at 45.degree. C.) and XXI
(stability studies at 55.degree. C.).
The percent of albuterol remaining in each patch versus time data
at 45.degree. C. and 55.degree. C. was then simultaneously fitted
to a nonlinear curve-fitting SAS computer program, which is known
by those of skilled in the art.
Following this, the values of k25.degree. C., k45.degree. C.,
k55.degree. C. and Ea were estimated using the SAS computer
program, where k is the "degradation rate constant" and Ea is the
"activation energy." From the value of k25.degree. C., shelf-like
(T85%, time required to reach 85% of the original potency) was
estimated using a nonlinear regression analysis and the statistical
computer program.
The "degradation rate constant," "activation energy" and
"shelf-life estimation" values are shown in Table XIX. It appears
that the "degradation rate constant" at 55.degree. C. is at least
three times faster than that at 45.degree. C., and at least 50 to
60 times faster than that at 25.degree. C. The activation energy is
approximately 25 KCal/mole.
It appears that the patches, when stored at 25.degree. C. would
maintain 85% of their original potency for 169-182 weeks according
to the "Mean Prediction Method," a method known by those of skill
in the art, and for 143-156 weeks according to the "One Sided 95%
Lower Confidence Level Prediction Method" (95% LCLPM), a method
also known by those of skill in the art. Moreover, according to 95%
LCLPM, it is predicted that future lots of the patches, when stored
at 25.degree. C., would maintain 85% of their original potency for
143-156 weeks.
In conclusion, from the stability experiments described above, it
was predicted that the transdermal albuterol patches of the
invention would retain a potency of 85% at ambient temperature over
a 2-year period.
TABLE I ______________________________________ In Vitro Hairless
Mouse Skin Permeation Rate Constants (In Vitro Release Rate
Constants) ______________________________________ (1) Single-Layer
Albuterol Transdermal Patch (Example 2) Mean = 0.50 mg .multidot.
cm.sup.-2 .multidot. day.sup.-1 (n = 3) Standard Deviation = 0.02
mg .multidot. cm.sup.-2 .multidot. day.sup.-1 (2) Double-Layer
Albuterol Transdermal Patch (Example 3) Mean = 0.45 mg .multidot.
cm.sup.-2 .multidot. day.sup.-1 (n = 6) Standard Deviation = 0.05
mg .multidot. cm.sup.-2 .multidot. day.sup.-1
______________________________________
TABLE II ______________________________________ In Vitro Albuterol
Transdermal Patch Dissolution Rate Constants (mg .multidot.
cm.sup.-2 .multidot. day.sup.-1)
______________________________________ (1) Single-Layer Albuterol
Transdermal Patch (Example 2) Mean = 2.34 mg .multidot. cm.sup.-2
.multidot. day.sup.-1 (n = 3) Standard Deviation = 0.14 mg
.multidot. cm.sup.-2 .multidot. day.sup.-1 (2) Double-Layer
Albuterol Transdermal Patch (Example 3) Mean = 2.37 mg .multidot.
cm.sup.-2 .multidot. day.sup.-1 (n = 6) Standard Deviation = 0.25
mg .multidot. cm.sup.-2 .multidot. day.sup.-1
______________________________________
TABLE III ______________________________________ Transdermal Patch
Analysis before and after Application to the Skin of Four Rhesus
Monkeys (#388, #391, #423 and #430) Amounts of Albuterol in
Transdermal Patch Mean Standard Deviation
______________________________________ (1) Single-Layer Albuterol
Transdermal Patch (Example 2) (1) Initial Amount 6.26 2.30 (mg
.multidot. cm.sup.-2) (n = 4) (2) Residual Amount 5.50 1.98 (mg
.multidot. cm.sup.-2) (n = 4) (3) Rhesus Monkey Skin 0.76 0.28
Permeation Rate (n = 4) Constant (In vitro Release Rate Constant)
(mg .multidot. cm.sup.-2 .multidot. day.sup.-1) (2) Double-Layer
Albuterol Transdermal Patch (Example 3) (1) Initial Amount 5.56
1.30 (mg .multidot. cm.sup.-2) (n = 3) (2) Residual Amount 3.60
0.82 (mg .multidot. cm.sup.-2) (n = 3) (3) Rhesus Monkey Skin 1.96
0.46 Permeation Rate (n = 3) Constant (In vitro Release Rate
Constant) (mg .multidot. cm.sup.-2 .multidot. day.sup.-1)
______________________________________
TABLE IV
__________________________________________________________________________
Serum Concentration Time Data following Intravenous Injection of 50
mcg/kg Albuterol in Rhesus Monkeys Time Monkey Monkey Monkey Monkey
Standard Hours #388 #391 #423 #430 Average Deviation
__________________________________________________________________________
0.00 0.00 0.00 0.00 0.00 0.08 102.00 73.60 84.30 73.00 57.72 38.83
0.17 40.70 56.90 46.80 45.00 47.35 8.40 0.33 23.70 39.70 29.10
31.60 31.02 6.65 0.75 13.20 17.90 19.60 16.60 16.82 2.71 1.00 10.60
18.70 14.30 13.80 14.35 3.33 1.50 8.00 12.50 14.60 11.20 11.58 2.76
2.00 8.74 11.50 12.70 9.66 10.65 1.78 3.00 5.63 7.55 12.30 8.32
8.45 2.80 4.00 5.43 6.33 7.84 6.04 6.41 1.02 5.00 6.82 4.53 7.59
4.13 5.77 1.70
__________________________________________________________________________
TABLE V
__________________________________________________________________________
Serum Concentration Time Data following Transdermal Application of
a Single-Layer Albuterol Patch in Rhesus Monkeys Time Monkey Monkey
Monkey Monkey Standard Hours #388 #391 #423 #430 Average Deviation
__________________________________________________________________________
0.0 0.00 3.69 0.00 0.00 0.5 3.03 0.00 0.00 0.00 1.0 0.00 0.00 0.00
0.00 1.5 0.00 0.00 0.00 0.00 3.0 4.87 3.90 0.00 2.67 2.86 2.11 5.0
11.00 11.40 6.94 4.39 8.43 3.36 7.0 20.90 22.60 18.40 9.15 17.76
6.00 12.0 29.00 31.60 45.50 27.50 33.40 8.24 24.0 29.40 31.10 74.30
67.40 50.55 28.92 31.0 8.47 10.70 20.00 17.70 14.21 6.74 48.0 0.00
8.74 2.90 4.26
__________________________________________________________________________
TABLE VI ______________________________________ Mean and Standard
Deviation of Pharmacokinetic Parameters obtained after Intravenous
Injection of a 50 mcg/Kg Albuterol Solution in Rhesus Monkeys Mean
Parameter (n = 4) Standard Deviation
______________________________________ (1) Area Under the 84.19
16.15 Curve (AUC) (ng .multidot. mL.sup.-1 .multidot. hour.sup.-1)
(2) Initial Half-Life 6.0 3.4 (minutes) (3) Terminal Half- 135.6
26.93 Life (minutes) (4) Terminal 0.0053 0.00094 Elimination Rate
Constant (minute.sup.-1) (5) Apparent Volume 1935.9 37.2 of
Distribution (mL .multidot. Kg.sup.-1) (6) Clearance (Cl) 10.2 1.8
(mL .multidot. minute.sup.-1 .multidot. Kg.sup.-1)
______________________________________
TABLE VII ______________________________________ Mean and Standard
Deviation of Pharmacokinetic Parameters obtained after Transdermal
Application of an Albuterol Transdermal Patch in Four Rhesus
Monkeys Mean Parameter (n = 4) Standard Deviation
______________________________________ (1) Single-Layer Albuterol
Transdermal Patch (Example 2) (1) Weight of the 5.39 0.025 monkey
(Kg) (2) Area Under 1070.6 394.10 the Curve (AUC) (ng .multidot.
mL.sup.-1 .multidot. hrs) (3) Steady State 42.0 14.45 Serum
Albuterol Concentration (C.sub.ss) (12-24 hrs) (ng .multidot.
mL.sup.-1) (4) Clearance (Cl) 10.2 1.8 (mL .multidot. minute.sup.-1
.multidot. Kg.sup.-1) (5) In vivo 0.81 0.20 Absorption Rate
Constant (K.sub.0) (mg .multidot. cm.sup.-2 .multidot. day.sup.-1)
(6) Skin Bioavailability 115 16 (F) of Albuterol (per cent (%))
______________________________________ Double-Layer Albuterol
Transdermal Patch (Example 3) (1) Weight of the 5.33 0.2 Monkey
(Kg) (2) Area Under 1500.80 191.47 the Curve (AUC) (ng .multidot.
mL.sup.-1 .multidot. hrs) (3) Steady State 57.9 2.16 Serum
Albuterol Concentration (C.sub.ss) (12-24 hrs) (ng .multidot.
mL.sup.-1) (4) Clearance (Cl) 9.78 1.99 (mL .multidot.
minute.sup.-1 .multidot. Kg.sup.-1) (5) In vivo 1.09 0.23
Absorption Rate Constant (K.sub.0) (mg .multidot. cm.sup.-2
.multidot. day.sup.-1) (6) Skin Bioavailability NC* NC* (F) of
Albuterol (per cent (%)) ______________________________________ *NC
-- Not Calculated
TABLE VIII
__________________________________________________________________________
Comparison of the In Vitro Rhesus Monkey Skin Permeation Rate
Constant and the In-Vivo Rhesus Monkey Absorption Rate Constant
(K.sub.0) after the Application of a Transdermal Albuterol Patch to
Rhesus Monkeys Rhesus Monkey Skin Permeation Rate Constant In Vivo
Rhesus Monkey Absorption (In Vitro Release Rate Constant) Rate
Constant (K.sub.0) (mg .multidot. cm.sup.-2 .multidot. day.sup.-1)
(mg .multidot. cm.sup.-2 .multidot. day.sup.-1) Mean Standard
Deviation Mean Standard Deviation
__________________________________________________________________________
Single- 0.76 0.28 .81 0.20 Layer Patch (n = 4) Double- 1.96 0.46
1.09 0.23 Layer Patch (n = 3)
__________________________________________________________________________
TABLE IX ______________________________________ Comparison of In
Vitro Parameters of Transdermal Albuterol Patches Standard
Parameter Table Mean Deviation
______________________________________ (1) Single-Layer Albuterol
Transdermal Patch (Example 2) Hairless Mouse Skin Table I 0.50 0.02
Permeation Rate (n = 3) Constant (mg .multidot. cm.sup.-2
.multidot. day.sup.-1) Dissolution Table II 2.34 0.14 Rate Constant
(n = 3) (mg .multidot. cm.sup.-2 .multidot. day.sup.-1) Rhesus
Monkey Table III 0.76 0.28 Skin Permeation (n = 4) Rate Constant
(mg .multidot. cm.sup.-2 .multidot. day.sup.-1)
______________________________________ (2) Double-Layer Albuterol
Transdermal Patch (Example 3) Hairless Mouse Skin Table I 0.45 0.05
Permeation Rate (n = 6) Constant (mg .multidot. cm.sup.-2
.multidot. day.sup.-1) Dissolution Table II 2.37 0.25 Rate Constant
(n = 3) (mg .multidot. cm.sup.-2 .multidot. day.sup.-1) Rhesus
Monkey Table III 1.96 0.46 Skin Permeation (n = 3) Rate Constant
(mg .multidot. cm.sup.-2 .multidot. day.sup.-1)
______________________________________
TABLE X
__________________________________________________________________________
Comparison of Hypothetical Human Serum Albuterol Concentrations
from Transdermal Albuterol Patches Versus Literature-Reported
Concentrations of Albuterol Tablets in a 70 Kg Human Being Serum
Concentration of Various Albuterol Formulations Single-Layer Patch
Double-Layer Patch Controlled-Release Instant-Release (IR) (every
24 hours) (every 24 hours) Table Formulation Tablet Formulation*
Serum Concen- Patch Patch (8 mg of albuterol (4 mg of albuterol
tration (mg/mL) Size (cm.sup.2) Serum Concentration (mg/mL) Size
(cm.sup.2) 12 hours) (ng/mL) every 6 hours)
__________________________________________________________________________
(ng/mL) 2-4 4 3-5 4 11.0 11.1 4-8 8* 6-10 8* 8-16 16 12-20 16
__________________________________________________________________________
*Approximately 6 mg of albuterol permeated from an 8 square
centimeter patch.
TABLE XI ______________________________________ Dose Versus Area
Under the Curve Comparison following Intravenous and Transdermal
Patch Application of Albuterol in Rhesus Monkeys Parameter Mean
Standard Deviation ______________________________________ (1)
Intravenous* 0.05 0.0 Dose (mg .multidot. Kg.sup.-1) (n = 4) (2)
Transdermal** 0.76 0.28 Dose: Single- Layer Patch (mg .multidot.
Kg.sup.-1) (n = 4) (3) Transdermal Dose:** NC*** NC*** Double-Layer
Patch (mg .multidot. Kg.sup.-1) (n = 3) (4) Area Under the 84.19
16.15 Curve (AUC) after Intra- venous Administration (ng .multidot.
mL.sup.-1 .multidot. hour.sup.-1) (n = 4) (5) Area Under the 1070.6
394.1 Curve (AUC) after Single-Layer Transdermal Patch
Administration (ng .multidot. mL.sup.-1 .multidot. hour.sup.-1) (n
= 4) (6) Area Under the Curve 1500.80 191.47 (AUC) after
Double-Layer Transdermal Patch Administration (ng .multidot.
mL.sup.-1 .multidot. hour.sup.-1 ) (n = 3)
______________________________________ *Amount of albuterol
injected into each of the Rhesus monkeys. **Calculated from the
Rhesus monkey "skin permeation rate constants" ("in vitro release
rate constants") in Table III. ***NC--Not Calculated
TABLE XII ______________________________________ Serum
Concentration Time Data following Transdermal Appli- cation of a
Double-Layer Albuterol Patch in Rhesus Monkeys Time Monkey Monkey
Monkey Hours #388 #391 #423 Average S.D.
______________________________________ 0.0 0.000 0.287 0.000 0.5
0.000 0.000 0.000 1.0 0.000 0.000 0.000 1.5 0.000 0.000 0.779 0.26
0.45 3.0 1.270 2.270 8.790 4.11 4.08 5.0 24.200 14.900 25.100 21.40
5.64 7.0 44.700 22.200 33.200 33.36 15.91 12.0 58.500 42.900 53.400
51.60 7.95 24.0 59.300 68.100 65.600 64.33 4.53 31.0 10.900 26.900
33.300 23.70 11.54 48.0 0.000 0.000 0.000 0.00 0.00
______________________________________
TABLE XIII ______________________________________ Rabbit Dermal
Irritation Grading System Value
______________________________________ A. Erythema (1) No erythema;
0 (2) Very slight erythema (barely perceptible); 1 (3) Well-defined
erythema; 2 (4) Moderate to severe erythema; and 3 (5) Severe
erythema (beet redness) to slight 4 eschar formations (injuries in
depth) B. Edema (1) No edema; 0 (2) Very slight edema (barely
perceptible); 1 (3) Slight edema (edges of area well defined 2 by
definite raising); (4) Moderate edema (raised approximately 1 mm);
3 and (5) Severe edema (raised more than 1 mm 4 extending beyond
the area of exposure). ______________________________________
TABLE XIV ______________________________________ Dermal Evaluation
Criteria Primary Irritation Index* (P.I.I.) Irritation Rating
______________________________________ 0.00 Nonirritant 0.01-0.49
Negligible Irritant 0.50-1.99 Slight Irritant 2.00-4.99 Moderate
Irritant 5.00-8.00 Strong Irritant
______________________________________ *Mean Primary Irritation
Index = 2.83 (n = 6)
TABLE XV
__________________________________________________________________________
Scores Obtained From the Rabbit Skin Irritation Tests Scoring Score
Parameter Interval 7658/M 7661/M 7708/F 7687/F 7689/F 7692/F
__________________________________________________________________________
A. Erythema 24 hours 2 2 2 1 2 2 72 hours 4* 2 2 0 1 2 7 days 1**
1** 0 -- 0 0 B. Edema 24 hours 2 1 1 1 1 2 72 hours 1 1 0 0 1 1 7
days 0 0 0 -- 0 0
__________________________________________________________________________
*Blanching **Desquamation
TABLE XVI ______________________________________ Data Obtained from
the Guinea Pig Dermal Dose Range Finding Studies Score Animal 24
Hour 48 Hour ______________________________________ 4648/Male .+-.
.+-. 4649/Male .+-. 0 ______________________________________
TABLE XVII ______________________________________ Data Obtained
from the Guinea Pig Dermal Sensitization Induction Studies (n = 15)
24-Hour 48-Hour Mean .+-. Mean .+-. Standard Standard Induction #
Deviation Deviation ______________________________________ 1 0.0
.+-. 0.0 0.0 .+-. 0.0 2 0.0 .+-. 0.0 0.0 .+-. 0.0 3 0.3 .+-. 0.1
0.0 .+-. 0.0 4 0.0 .+-. 0.0 0.0 .+-. 0.0 5 0.3 .+-. 0.1 0.0 .+-.
0.0 6 0.3 .+-. 0.1 0.0 .+-. 0.0 7 0.3 .+-. 0.1 0.0 .+-. 0.0 8 0.0
.+-. 0.0 0.0 .+-. 0.0 9 0.1 .+-. 0.2 0.0 .+-. 0.0
______________________________________
TABLE XVIII ______________________________________ Data Obtained
from the Guinea Pig Dermal Sensitization Challenge Studies Dermal
Score (Mean .+-. Standard Deviation) Animals 24 Hour 48 Hour
______________________________________ Test Guinea Pigs (n = 15)
0.3 .+-. 0.3 0.1 .+-. 0.2 Control Guinea Pigs (n = 5) 0.0 .+-. 0.0
0.0 .+-. 0.0 ______________________________________
TABLE XIX ______________________________________ Parameters
Generated from Stability Studies Parameter Value
______________________________________ (1) Degradation Rate 0.00096
.+-. 0.00011 Constant (k) Mean Standard Deviation at 25.degree. C.
(k25.degree. C.) (n = 3) (1/week) (2) Degradation Rate 0.01603 .+-.
0.00063 Constant (k) Mean Standard Deviation at 45.degree. C.
(k45.degree. C.) (n = 3) (1/week) (3) Degradation Rate 0.05759 .+-.
0.00096 Constant (k) Mean Standard Deviation at 55.degree. C. (n =
3) (1/week) (4) Arrhenius 26.54 .+-. 0.74 Activation Mean Standard
Deviation Energy (Ea) (n = 3) (kCal/mole) (5) Mean (n = 3) 169-182
Weeks Prediction of (Mean Prediction Method) Time Required to
143-156 Weeks Reach 85% of the (One Sided 95% Lower Confidence
Original Potency Level Prediction Method) (T85%) at 25.degree. C.
143-156 Weeks (Weeks) (One Sided 95% Lower Confidence Level
Prediction Method for Future Samples)
______________________________________
TABLE XX ______________________________________ Stability Studies
of Albuterol Transdermal Patches at 45.degree. C. Recovery of
Albuterol from Patch Sample Mean and Standard Deviation Time
(Percent) (n = 3) (Percent) ______________________________________
(1) 0 Weeks 99.77 100.39 .+-. 0.864 101.00 (2) 3 Weeks 94.12 96.31
.+-. 2.91 99.61 95.19 (3) 6 Weeks 90.18 90.27 .+-. 0.58 89.74 90.88
(4) 9 Weeks 86.47 86.65 .+-. 0.94 87.66 85.81 (5) 12 Weeks 82.82
83.06 .+-. 1.27 81.94 84.43
______________________________________
TABLE XXI ______________________________________ Stability Studies
of Albuterol Transdermal Patches at 55.degree. C. Recovery of
Albuterol from Patch Sample Mean and Standard Deviation Time
(Percent) (n = 3) (Percent) ______________________________________
(1) 0 Weeks 99.77 100.39 .+-. 0.864 101.00 (2) 2 Weeks 89.51 88.83
.+-. 1.10 87.56 89.42 (3) 6 Weeks 73.21 71.33 .+-. 3.67 67.11 73.67
(4) 12 Weeks 41.94 50.14 .+-. 7.12 53.67 54.80
______________________________________
In summary, the results of Experiments 1(a)-(i) conducted with the
transdermal albuterol patches described in Examples 2
(single-layer), 4 (single-layer) and 3 (double-layer) below showed
an in vivo - in vitro correlation, a 100% albuterol skin
bioavailability, sustained serum drug concentrations for 24 hours
upon a once-a-day patch application, ease of administration of the
patches, little or no skin irritation at the patch application site
in either Rhesus monkeys or rabbits and good stability over a
2-year shelf life. In addition, Experiment 1(h) showed that these
patches are not contact sensitizers in quiena pigs.
EXAMPLE 2
Preparation of Single Layer Transdermal Patch
100 g of an albuterol patch formulation was prepared With 71.81 of
Dow X7-3058 Silastomer.TM. elastomeric matrix material:Dow X7-3059
crosslinking agent (97.86:2.I4), 15.98 g of nonmicronized
albuterol, 9.99 g of n-dodecanol, 1.75 g of glycerol, 0.35 g of
hexanol and 0.125 g of X7-3075 catalyst.
In a clean mortar, the catalyst was mixed with the matrix material
and crosslinking agent in a geometric dilution.
In a separate clean mortar, a fine paste of albuterol, n-dodecanol,
hexanol and glycerol was made by combining and mixing the
above-described amounts of these transdermal patch components. One
portion of the matrix material-crosslinking agent-catalyst blend
was then mixed thoroughly with the albuterol paste. Following this,
the remaining two portions of the matrix material-crosslinking
agent-catalyst blend were mixed one at a time with the matrix
material-crosslinking agent-catalyst blend-albuterol paste.
The resulting mass was passed through a triple roller mill to
obtain a homogeneous mixture. (A homogeneous mixture of the mass
may be obtained by any suitable method, or with the use of any
suitable equipment, as known by those of skill in the art.)
The mixture was then placed between two sheets of mylar plastic
film (3M Corporation, St. Paul, Minn.), and passed through twin
aluminum rollers of a film casting apparatus built by Applicants to
adjust the thickness of the mixture to 0.3 mm by manipulating the
gap between the two rollers of the apparatus to 0.3 mm. (The
thickness of the mixture can be adjusted by any conventional film
casting apparatus or other suitable equipment, as known by those of
skill in the art.)
The resulting spread was then cured in an oven at 80.degree. C. for
25 minutes.
The cured film was then cut into several pieces (from 1 to 16
square centimeters), and each piece was then separately glued with
355 Medical Adhesive (Dow Corning, Inc.) onto a piece of aluminum
foil of corresponding size. The surface of the foil not in contact
with the film was then adhered to a piece of adhesive-lined foam
backing (Fasson, Painvile, Ohio) of corresponding size with 355
Medical Adhesive.
EXAMPLE 3
Preparation of Double Layer Transdermal Patch
A double-layer formulation transdermal albuterol patch of the
invention was made, having separate albuterol and dodecanol
layers.
100 g of an albuterol transdermal patch layer was prepared as
described below using 73.875 g of Dow X7-3058 Silastomer.TM. matrix
material:Dow X7-3059 crosslinking agent (97.86:2.14), 20 g of
nonmicronized albuterol, 5.0 g of glycerol, 1.0 g of hexanol and
0.125 g of Dow X7-3075 catalyst.
100 g of an n-dodecanol transdermal patch layer was separately
prepared as described below using 89.875 g of Dow X7-3058
Silastomer.TM. matrix material:Dow X7-3059 crosslinking agent
(97:86:2.14), 10 g of n-dodecanol and 0.125 g of catalyst.
For each layer, catalyst was first mixed with the matrix material
and crosslinking agent in a geometric dilution in a clean mortar to
form a matrix material-crosslinking agent-catalyst blend.
In a separate clean mortar, a fine paste of albuterol, hexanol and
glycerol was made using the above-described amounts of these
transdermal patch components. One portion of the first matrix
material-catalyst blend was mixed thoroughly with the albuterol
paste. Following this, the remaining two portions of the first
matrix material-catalyst blend were mixed one at a time with the
matrix material-crosslinking agent-catalyst blend-albuterol
paste.
The n-dodecanol transdermal patch layer was prepared separately by
mixing the n-dodecanol described above with the other matrix
material-crosslinking agent-catalyst blend.
The resulting masses of the albuterol and n-dodecanol layers were
separately processed as follows. Each mass was passed through the
triple roller mill described in Example 2 to obtain a homogeneous
mixture. Each mixture was then separately placed between two sheets
of mylar plastic film, as described above in Example 2, and passed
through two aluminum rollers of the film casting apparatus
described in Example 2. Each resulting spread was then cured in an
oven at 80.degree. C. for 25 minutes.
The cured albuterol and n-dodecanol film layers were then cut into
pieces, each measuring from 1 to I6 square centimeters. Each
n-dodecanol layer was then placed upon an albuterol layer of
corresponding size, and adhered naturally thereto.
The surface of the n-dodecanol layer not in contact with the
albuterol layer was then glued to a piece of aluminum foil of
corresponding size with 355 Medical Adhesive.
The surface of the foil not in contact with the n-dodecanol layer
was then adhered to a piece of adhesive-lined foam backing (Fasson,
supra.) of corresponding size with 355 Medical Adhesive.
EXAMPLE 4
Preparation of Single Layer Transdermal Patch (Preferred Method of
Preparation)
Using the same materials set forth in Example 2, with the exception
of the substitution of micronized albuterol for nonmicronized
albuterol, and the same quantities thereof, single-layer
transdermal albuterol patches of the invention were prepared in the
following manner.
In a clean mortar, the Dow X7-3058 Silastomer.TM. elastomeric
matrix material was mixed with X7-3059 crosslinking agent in the
proportion of 97.86:2.14. This mixture was then aged for two days
prior to use. (It should be aged for not less than 2, and not more
than 7, days prior to use.)
In a separate clean container, the albuterol, n-dodecanol,
glycerol, hexanol and catalyst were mixed with a spatula to make a
fine paste.
Then, the matrix material-crosslinking agent blend was added to the
other mixture and mixed thoroughly in a porcelain mortar with a
pestle.
The resulting mixture was then passed twice through the triple
roller mill described in Example 2.
An aliquot of the mixture was then transferred into a syringe which
had had its tip cut. (The size of the aliquot is not critical, and
may vary according to the size of the syringe employed.) The
aliquot of the mixture was then placed between two sheets of mylar
plastic film (3M Corporation) with the syringe.
From this point on, this experiment was conducted in the manner
described in Example 2.
This method is preferable to the method described in Example 2 for
preparing single-layer transdermal albuterol patches of the present
invention.
Therapeutically-active agents which produce a systemic activity,
and which are deliverable by the present invention are, for
instance, and without limitation, anti-infectives, for example
pentamidine and lomefloxacin, antibiotics, for example
metronidazole, hormones, antipyretics, antidiabetics, coronary
dilation agents, glycosides, spasmolytics, antihypertensives, for
example verapamil and its enantiomers and betaxolol, psychoactive
agents, for example zolpidem, cycloserine and milacemide,
corticosteroids, analgesics, contraceptives, nonsteroidal
anti-inflammatory drugs, for example oxaprozen, antioholinergics,
sympatholytics, sympathomimetics, vasodilatory agents,
anticoagulants, antiarrhythmics, for example disopyramide or
disobutamide, and prostaglandins having various pharmacologic
activities, for example misoprostol and enisoprost.
While the transdermal patches of the present invention have been
described and illustrated herein some specifivity, and with
reference to certain prepared embodiments thereof, those skilled in
the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages of
active agent other than the preferred ranges set forth hereinabove
may be applicable as a consequence of variations in the
responsiveness of the patient being treated, dosage-related adverse
effects, if any, and analogous considerations. Likewise, the
specific pharmacological responses observed may vary according to,
and depending upon, the particular active compounds selected for
incorporation into the patches. Such expected variations and/or
differences in the results are contemplated in accordance with the
objects and practices of the present invention. It is intended
therefore that all of these modifications and variations be within
the scope of the present invention as described and claimed herein,
and that the invention be limited only by the scope of the claims
which follow, and that such claims be interpreted as broadly as is
reasonable.
* * * * *